Prelude

This webpage began with a focus upon Yersinia enterocolitica and other
intracellular bacteria, but soon I realized that HHV6 and CMV have similar
immune-impairing effects by virtue of persistently infecting monocytes. Thus,
as of now, this webpage rambles along diversely, presenting citations about
Yersinia, other bacteria, HHV6, and CMV. This page is but a crudely shaped
building block for additional research regarding intra-monocyte infections.

Summary

This webpage presents information about Yersinia, Leishmania, and Plasmodium
species, as well as HHV6 and CMV, and their immune-impairing effect upon
monocytes. Intestinal and extra-intestinal aspects of Yersinia enterocolitica
are discussed, and also presented is information about a diagnostic test which
can identify significant Yersinia presence. There are intra-monocyte pathogens
other than those mentioned on this webpage, but the citations presented here
convey principles whereby intra-monocyte infections can affect hematopoiesis,
immunity, and the blood-brain "barrier". A second webpage is linked hereinbelow
and focuses upon cross-reactivity and thyroid-related autoimmune aspects of
Yersinia enterocolitica

Yersinia enterocolitica & lab tests

Recently, Yersinia entercolitica came to my attention via an autism-
spectrum child's medical data which, in toto, comprised one of the more thorough
compilations sent me thus far. My initial analysis of that data can be found on
several interlinked webpages. http://www.jorsm.com/~binstock/mike-1.htm
     Given the caveat that PCR of monocytes for CMV has yet to be performed for
this child, his data revealed no obvious signs of viral participation; however,
a Great Smokies microbiology panel indicated heavy intestinal colonizations by
Klebsiella pneumoniae and hemolytic Escherichia coli. Fortunately, he is showing
steady cognitive and behavioral improvement by a therapeutic protocol that
includes but is not limited to gastrointestinal remedies.
     Soon after I wrote the aforementioned report, his parents received data
from additional lab panels including the "ulcerative colitis and inflammatory
bowel disease" (UCibd) panel (ImmunoSciences Lab, Inc), which reports IgM, IgA,
and IgG antibodies against Klebsiella, Yersinia enterocolitica, bacterial
endotoxins and exotoxins, and Clostridium difficile toxin, as well as IgG
against Tropomyosin ($212.50 in its recent catalog). Mike's UCibd panel showed
high titers against Yersinia enterocolitica, higher even than his titers against
Klebsiella pneumoniae, which Great Smokies had demonstrated to be deeply
colonized within Mike's gastrointestinal tract. 
     That Yersinia enterocolitica, apparently, is not identified by the Great
Smokies microbiology panel seems extremely important (23) given that Yersinia
enterocolitica is associated with impaired monocyte function and with bacterial
and fungal infections, including within mucosal surfaces, and often appearing
during the first year of life (1-2, 5).

Consider some quotes from Pizzo and Meuller (2):

     "The skin and mucosal surfaces represent the primary defense against
     both endogenous and exogenous sources of infection."

     "In addition to mucosal breakdown, mechanical obstruction [eg,
     prolonged constipation] can also increase the risk of serious
     localized infection due to stasis of local body fluids and resultant
     overgrowth of potentially pathological colonizing organisms."

     "The polymorphonuclear leukocyte [ie, neutrophil] and the monocyte
     are the two most important components of cellular host defense that
     protect against invasive bacteria and fungi."

     "A number of... disorders are characterized by defects in chemotaxis
     of either or both granulocytes and monocytes..."

     "Colonization of the patient often precedes infection, as evidenced
     by a decrease in the 'normal flora' and an increase in aerobic gram-
     negative bacteria."

     "The most common gram-negative bacteria associated with infection in
     compromised hosts are Escherichia coli and Klebsiella species.", but
     many other bacteria and fungi can attain colonization in the presence
     of various cell-mediated immune defects, whether genetic or acquired;
     the list of additional pathogens that might appear in any given
     autism-spectrum child is quite long and includes, but is not limited
     to, Candida and Aspergillus species, Histoplasma capsulatum,
     Cocidioides immitis, as well as Citrobacter and other species.

Lab tests and more lab tests

There are two principles worth noting here. 
     First, even as the Great Smokies microbiology panel provides data that
turns out to be extremely important some autism-spectrum children, that panel
(like virtually all lab-test panels) is not inclusive; and, as the example of
Mike's subsequent data indicates, additional gastro panels can augment the Great
Smokies microbiology panel, eg, ImmunoScience Lab, Inc.'s "ulcerative colitis
and inflammatory bowel disease" panel and the "gastrointestinal evaluation
panel" can provide additional and, for some children, quite instructive
information.
     Second, persisting intracellular infection by Yersinia species can result
in an ongoing immune impairment due to altered monocyte function (1,5), and a
child with such an intracellular infection is likelier to have persisting
colonizations by other pathogens (1,2).

Consider some quotes and concepts from Neil Reiner's article (1):

     from the abstract, "Given the critical antimicrobial properties of
     mononuclear phagocytes [ie, monocytes], an important concern... has
     been to understand how intracellular microbes are able to establish
     states of chronic infection within these cells. Recent studies
     indicate that mononuclear phagocytes become functionally deactivated
     during intracellular infection... [there is a growing amount of]
     experimental evidence to indicate that this is a frequent event that
     may be accounted for by induced defects in the signaling pathways
     required to bring [these] cells to an activated state."

     Reiner mentions three ways that monocytes and macrophages can be de-
     activated, two mechanisms being what he calls "passive mechanisms"
     (3), and "deactivation... via the inducction of autoinhibitory
     cytokines... IL-10... TGF-beta" (4). Instead, his review focuses upon
     how these "intracellular pathogens... [eg, Yersinia, Leshmania, and
     Myobacteria that] actively alter cell signalling that lead to
     mononuclear phagocyte deactivation."

Leishmania (1)

     "Leishmanial infection of mononuclear phagocytes results in enhanced
     production of the autoinhibitory molecules prostaglandin E2 (PGE2)...
     and TGF-beta... results in defective interferon-gamma... induced
     expression of ... MHC... class II genes..., decreased
     lipopolysaccharide-induced IL-1 production... [etc] 

     "...Leishmania represents another system in which the
     pathogen/mononuclear-phagocyte interaction is pivotal and in which
     cell deactivation is observed..." 

     "Leishmania infections are transmitted to humans when vector
     sandflies take a blood meal..."

Myobacteria (1)

     "Deactivation of mononuclear phagocytes contributes to the
     pathogenesis of infection with Myobacteria... mononuclear phagocytes
     infected with viable Myobacteria are refractory to the activating
     properties of IFN-gamma for induction of microbicidal activity..." In
     other words, IFN-gamma function is impaired in monocytes and
     macrophages infected with Mulbacteria.

Yersinia (1)

     "Yersinia are another example of organisms that deactivate
     mononuclear phagocytes. Although these bacteria are found within
     [these cells] in tissues from infected hosts, Yersinia largely
     proliferate extracellularly within the reticuloendothelial system...
     Recent evidence suggests that Yersinia-induced inhibition of
     phagocytosis is an active process that disrupts the intracellular
     signaling events involved in pathogen ingestion."

     "Early after infection, pathogenic Yersinia re ingested by
     neutrophils and mononuclear phagocytes and, at least within the
     latter cells, they are resistant to elimination. On the other hand,
     once released from mononuclear phagocytes, Yersinia are found to be
     relatively resistant to phagocytosis..."

     Yersinia have the "ability to impair the mononuclear phagocyte cell
     signaling that is required for phagocytosis and perhaps other
     effector activities."

Additional considerations from Yersinia enterocolitica literature

[a]  Whether or not Mike has a chronic active Yersinia infection or instead has
a persistence of Yerisinia-derived polysaccharide fragments is not known (6-8).
[b]  Bone marrow macrophages and cytokine-production therefrom can be affected
by intra-macrophage Yersinia (7-8).
[c]  Yersinia's immune-impairing capabilities are increasingly documented (eg,
9-13).
[d]  "Lipoprotein from Yersinia enterocolitica contains epitopes that
cross-react
with the human thyrotropin receptor." (14)
[e]  Yersinia alters spicing of transcripts derived from HLA-B27 (eg, 15-16).
[f]  Yersinia can induce Stem Cell Factor in endothelial cells and thereby
contribute to inflammation (17). This finding has potential importance in that
(a) the cerebral vasculature we think of as part of the blood-brain "barrier"
is, to a goodly extent, comprised of endothelial cells, and (b) monocytes enter
tissues of the bbb, and some such monocytes even progress farther through and
then become perivasular microglia (WF Hickey et al, series of studies).
Endothelial infection by Yersinia-infected monocytes has been documented (17b).
[g]  Persisting Yersinia infections can be localized, eg, within abdominal lymph
nodes (18), and various intestinal and extraintestinal locations (19). Yersinia
is also has been documented in some individuals with collagenous colitis and
duodenal villous atrophy not responsive to gluten-free diets (20); and even
"non-virulent" strains of Y. enterocolitica can induce pathology in some
individuals (21). To some extent, clinical portraits vary with age (22).

Nosocomial infections

Nosocomial Yersinia infections have been documented, thus placing Yersinia
alongside Clostridium difficile (and many et cetera) as pathogens often acquired
in hospitals (2,24). Surprisingly and unfortunately, washing hands when
proceeding from one patient to another remains a major flaw in modern medicine
(25)

     "The toxin of C. difficile can cause symptoms ranging from mild
     diarhea to pseudomembranous colitis... Several studies have suggested
     that nosocomial transmission is common, indicated by time-space
     clustering of incident cases with identical immunoblot types together
     with the finding of C. difficile on the hands of health care
     workers... This further underscores the importance of hand washing.
     (2).

     Despite the hand-washing lessons taught by the Ignaz Semmelweiss
     incident, "... a recent study -- conducted at the Duke University
     Medical Center and published last month in The Lancet... -- found
     that only 17 percent of physicians treating patients in an intensive
     care unit washed their hands appropriately..." (25)

     In the US, approximately 1.8 million people per year acquire an
     infection while hospitalized, and "Twenty thousand of them will die
     as a direct result, by contrast, 17,171 Americans died of AIDS in
     1998... The infections will cost $4.5 billion to treat, the C.D.C.
     estimates." (25)

CMV and HHV6 Monocytes can also be persistently infected with CMV or HHV6, which generate immune impairments similar to those of the intra-monocytes pathogens mentioned hereinabove. If not fully immunosuppressed, CMV and HHV6 also alter hematopoietic processes (26-42).

PCR for Yersinia etc Yersinia can be positively identified by PCR (eg, 43-46), a technique also used to identify HHV6 and CMV in monocytes.

Conclusion

Parents of autism-spectrum children ought be aware that, although the Great
Smokies microbiology panel provides important information, some pathogen
categories are omitted. Furthermore, a pathogen can establish residence is some
body compartments and yet not be present in stool samples and/or not identified
by stool-culture processes. Yersinia, HHV6, and CMV are examples of pathogens
that are more likely to be indentified by other testing processes -- eg,
antibodies levels; and pathogens such as these are is very important because of
their detrimental effects upon monocyte function and, thereby, their varied
roles in allowing other infections to have greater effect. Futhermore, Yersinia
and other pathogens can induce endothelial inflammation, thereby having the
potential to affect the blood-brain "barrier". All in all, knowing the monocyte-
pathogen status of an autism-spectrum child seems to be an important addition
to his or her medical profile.

References

1. Reiner NE. Altered cell signaling and mononuclear phagocyte deactivation
during intracellular infection. Immunology Today 15.8.374-381 1994.
2. Pizzo PA, Mueller BU. Chapter 48, Infectious complications in children with
hematologic disorders, p1738-1759, in: Nathan and Oski's Hematology of Infancy
and Childhood, 5th edition, v2; Saunders, 1998.
3. Hall BF, Joiner KA. Immunology Today 12.A22-A27 1991.
4. Bogdan C, Nathan C. Annals NY Acad Sci 685.713-39 1993.
5. Bliska JB et al. Cell 73.903-20 1993. [a major Yersinia study]

6. Arthritis Rheum 1998 May;41(5):855-62 
Persistence of Yersinia antigens in peripheral blood cells from patients with
Yersinia enterocolitica O:3 infection with or without reactive arthritis.
Granfors K, Merilahti-Palo R, Luukkainen R, Mottonen T, Lahesmaa R, Probst P,
Marker-Hermann E, Toivanen P
National Public Health Institute, Turku, Finland.

OBJECTIVE: To assess the persistence of bacterial antigens in peripheral blood
cells from patients with Yersinia enterocolitica O:3-triggered reactive
arthritis (ReA). METHODS: Peripheral blood samples were obtained from 20
patients with Y. enterocolitica O:3 infection (11 with ReA and 9 without).
These samples were studied by immunochemical techniques for the presence of
Yersinia antigens at the beginning of infection and up to 4 years thereafter.
Synovial fluid samples from 6 of the 11 ReA patients were also studied.
RESULTS: The Yersinia antigens lipopolysaccharide and heat-shock protein (HSP)
were detected in peripheral blood mononuclear cells and polymorphonuclear
phagocytes from all patients studied at the early phase of the disease. They
were also found in the synovial fluid cells of patients with Yersinia-triggered
ReA. At 4 years after the onset of infection, these bacterial antigens were
still detected in the peripheral blood cells of most of the ReA patients
studied. CONCLUSION: This study has, for the first time, directly demonstrated
that bacterial antigens persist for a long time in patients who develop ReA
after Y. enterocolitica O:3 infection. The finding of bacterial HSP in synovial
fluid cells could provide a link to the pathogenesis of ReA, since T cell
responses of synovial cells have been shown to be directed against that
structure. A close similarity between the bacterial and host HSP might
contribute to the development of the relatively common, chronic form of this
complication.
PMID: 9588737, UI: 98248151

7. J Infect Dis 1995 Aug;172(2):490-6 
Deferoxamine B but not deferoxamine G1 inhibits cytokine production in murine
bone marrow macrophages.
Autenrieth IB, Bohn E, Ewald JH, Heesemann J
Institut fur Hygiene und Mikrobiologie, Universitat Wurzburg, Germany.

The iron chelator deferoxamine (DFO) B enhances virulence of Yersinia
enterocolitica and modulates cellular immune responses. Since cytokines mediate
effector mechanisms in resolution of yersiniae from infected tissues, the
impact of DFO B and DFO G1 on cytokine production by murine bone marrow
macrophages (BMM) was investigated. BMM were stimulated with lipopolysaccharide
(LPS) of Salmonella typhimurium or infected with Y. enterocolitica. DFO B
inhibited interleukin (IL)-6, IL-12, and tumor necrosis factor (TNF)-alpha mRNA
production 4-fold (shown by semiquantitative reverse transcription polymerase
chain reaction). TNF-alpha and IL-6 protein production was reduced 50% by DFO
B. In contrast, DFO G1 had no effect on cytokine production. Moreover, cytokine
production by Yersinia-infected BMM was decreased by plasmid-encoded Yersinia
proteins. Thus, plasmid-cured strains induced higher cytokine responses in BMM
than did the wild type strain. These results suggest that DFO B acts in a
bimodal fashion in yersiniosis: iron supply to the pathogen and
immunosuppression of the host.
PMID: 7622893, UI: 95348549

8. Clin Infect Dis 1992 Oct;15(4):645-9 
Unusual manifestations of Yersinia enterocolitica infections diagnosed using
novel methods.
Tak PP, Visser LG, Hoogkamp-Korstanje JA, Kluin-Nelemans JC, Hogendoorn PC,
Kluin PM, Barza M, de Koning J, van Furth R
Department of Pathology, University of Leiden, The Netherlands.

We report the cases of two patients who had infections due to Yersinia
enterocolitica. The first patient exhibited chronic recurrent fever, hepatic
and splenic granulomas, and bone marrow abnormalities, and the second patient
presented with enterocolitis with leukocytoclastic vasculitis of the skin.
Cultures and agglutination titers were negative. Indirect immunofluorescence
techniques with use of serotype-specific antisera and antisera to Yersinia
outer-membrane proteins (Yops) were applied to biopsy specimens, and
immunoblotting techniques for determining class-specific circulating antibodies
to Yops were used for demonstrating these unusual manifestations of Y.
enterocolitica infections.

9. Infect Immun 1994 Oct;62(10):4445-53 
Essential role of YopD in inhibition of the respiratory burst of macrophages by
Yersinia enterocolitica.
Hartland EL, Green SP, Phillips WA, Robins-Browne RM
Department of Microbiology, University of Melbourne, Parkville, Victoria,
Australia.

The respiratory burst is a key element of the bactericidal armamentarium of
phagocytes. In this study we have shown that a virulent strain of Yersinia
enterocolitica serogroup O:9 coletely inhibited the ability of murine bone
marrow-derived macrophages to mount a respiratory burst in response to
stimulation by zymosan. This property of the bacterium was abrogated by curing
the strain of its 71.5-kb virulence plasmid and by transposon mutagenesis of
the plasmid-borne yopD gene. Derivatives of the bacterium which were unable to
inhibit the respiratory burst were also less able to disrupt cytoskeletal actin
and to resist phagocytosis. yopD mutants also showed an impaired ability to
dephosphorylate phosphotyrosine residues in macrophage proteins and were
completely avirulent for mice. All of these defects were fully or partly
restored by trans-complementation of a yopD mutant with a cloned yopD gene. The
results of this study and those of previous work with YopD (R. Rosqvist, A.
Forsberg, and H. Wolf-Watz, Infect. Immun. 59:4562-4569, 1991) suggest that
YopD functions chiefly by facilitating the transport of virulence
plasmid-encoded proteins, such as YopE, a cytotoxin, and YopH, a protein
tyrosine phosphatase, across the cytoplasmic membrane to their targets within
host cells. The combined action of these Yops on cytoplasmic proteins,
especially actin, could explain the effects of virulent Y. enterocolitica on
macrophage morphology, phagocytic capacity, and respiratory burst activity, all
of which rely on cytoskeletal integrity to function normally.

10. J Leukoc Biol 1995 Jun;57(6):972-7 
Role of YopH in the suppression of tyrosine phosphorylation and respiratory
burst activity in murine macrophages infected with Yersinia enterocolitica.
Green SP, Hartland EL, Robins-Browne RM, Phillips WA
University of Melbourne Department of Surgery, Western Hospital, Australia.

Tyrosine phosphorylation is an important component of the signaling pathways
responsible for the activation of the macrophage respiratory burst. Because the
virulence plasmid of Yersinia enterocolitica encodes a phosphotyrosine
phosphatase, YopH, it is possible that the pathogenic strategy of Y.
enterocolitica involves the disruption of tyrosine phosphorylation in the
macrophage leading to inhibition of respiratory burst activity. We have
investigated the effects of Yersinia infection on tyrosine phosphorylation and
respiratory burst activity in murine bone marrow-derived macrophages. Infection
of macrophages with virulent [Ye(pYV+)] but not avirulent [Ye(pYV-)] strains of
Y. enterocolitica was found to suppress both tyrosine phosphorylation and
respiratory burst activity in response to zymosan. Mutational inactivation of
YopH reversed the suppressive effect of Ye(pYV+) on zymosan-induced tyrosine
phosphorylation, indicating that YopH is responsible for the dephosphorylation
of macrophage phosphotyrosine-containing proteins observed in macrophages
infected with the virulent strain of Y. enterocolitica. In contrast, mutational
loss of YopH failed to reverse the inhibitory effect of Ye(pYV+) on the
zymosan-triggered respiratory burst. We conclude that the inhibition of the
macrophage respiratory burst by Y. enterocolitica involves a plasmid-encoded
virulence protein(s) other than, or in addition to, YopH.

11. Infect Immun 1997 Nov;65(11):4813-21 
Interaction of Yersinia enterocolitica with macrophages leads to macrophage
cell death through apoptosis.
Ruckdeschel K, Roggenkamp A, Lafont V, Mangeat P, Heesemann J, Rouot B
INSERM U431, Universite Montpellier II, France.

Suppression of the host defense is one of the hallmarks of Yersinia
enterocolitica infection. This enteric pathogen resists phagocytosis and
interferes with macrophage functions from an extracellular localization
(oxidative-burst generation and tumor necrosis factor alpha production). In
this study, we investigated the fate of the Y. enterocolitica-infected
macrophage. We found that murine J774A.1 macrophages and macrophages derived
from human monocytes were killed by infection with Y. enterocolitica. Analysis
of cellular morphology and DNA fragmentation revealed that macrophage cell
death occurs through the induction of apoptosis. A total of 92% +/- 5% (mean
+/- standard deviation) of murine J774A.1 macrophages and 74% +/- 6% of human
monocyte-derived macrophages underwent apoptosis upon Yersinia infection after
4 and 20 h, respectively. The broad-spectrum caspase inhibitor
Z-Val-Ala-DL-Asp-fluoromethylketone blocked completion of the Yersinia-induced
apoptotic program but not the surface exposure of phosphatidylserine as an
early-stage apoptotic event. Analysis of different Yersinia mutants showed that
macrophage apoptosis depends on a functional Y. enterocolitica type III protein
secretion system. Apoptotic cell death of macrophages was not related to the
YopE-mediated cytotoxic effect of Yersinia, since disruption of actin
microfilaments by a Y. enterocolitica strain expressing a restricted repertoire
of yop genes, including YopE, did not result in macrophage apoptosis.
Furthermore, Yersinia-induced cytotoxic alterations in epithelial HeLa cells,
which are conferred by YopE, did not lead to apoptosis. Our data demonstrate
for the first time that Y. enterocolitica promotes the apoptosis of
macrophages, an effect which is clearly distinct from the morphological
alterations mediated by Yersinia on epithelial HeLa cells.

12. Proc Natl Acad Sci U S A 1997 Sep 16;94(19):10385-90 
Yersinia signals macrophages to undergo apoptosis and YopJ is necessary for
this cell death.
Monack DM, Mecsas J, Ghori N, Falkow S
Department of Microbiology and Immunology, Stanford School of Medicine,
Stanford University, Stanford CA 94305, USA.

Pathogenic Yersinia spp. carry a large common plasmid that encodes a number of
essential virulence determinants. Included in these factors are the
Yersinia-secreted proteins called Yops. We analyzed the consequences of
wild-type and mutant strains of Yersinia pseudotuberculosis interactions with
the macrophage cell line RAW264. 7 and murine bone marrow-derived macrophages.
Wild-type Y. pseudotuberculosis kills approximately 70% of infected RAW264.7
macrophages and marrow-derived macrophages after an 8-h infection. We show that
the cell death mediated by Y. pseudotuberculosis is apoptosis. Mutant Y.
pseudotuberculosis that do not make any Yop proteins no longer cause host cell
death. Attachment to host cells via invasin or YadA is necessary for the cell
death phenotype. Several Yop mutant strains that fail to express one or more
Yop proteins were engineered and then characterized for their ability to cause
host cell death. A mutant with a polar insertion in YpkA Ser/Thr kinase that
does not express YpkA or YopJ is no longer able to cause apoptosis. In
contrast, a mutant no longer making YopE or YopH (a tyrosine phosphatase)
induces apoptosis in macrophages similar to wild type. When yopJ is added in
trans to the ypkAyopJ mutant, the ability of this strain to signal programmed
cell death in macrophages is restored. Thus, YopJ is necessary for inducing
apoptosis. The ability of Y. pseudotuberculosis to promote apoptosis of
macrophages in cell culture suggests that this process is important for the
establishment of infection in the host and for evasion of the host immune
response.

13. Res Microbiol 1994 May;145(4):297-307 
Properties of Yersinia enterocolitica porins: interference with biological
functions of phagocytes, nitric oxide production and selective cytokine
release.
Tufano MA, Rossano F, Catalanotti P, Liguori G, Marinelli A, Baroni A,
Marinelli P
Istituto di Microbiologia, Facolta di Medicina e Chirurgia, Seconda Universita
degli Studi di Napoli, Italy.

We have extracted and purified Yersinia enterocolitica ATCC 9610 porins that
have molecular weights of 36-38 kDa. They inhibited phagocytosis and
phagosome-lysosome fusion (30%) in human monocytes and caused enhanced nitrite
production. Preincubation of polymorphonuclear neutrophils with porins (1-10
micrograms/ml/10(6) cells) induced a reduction in chemotaxis, adherence to
nylon wool and chemiluminescence. Human lymphomonocytes treated with Y.
enterocolitica porins showed a distinctive cytokine profile. Interleukin-1
alpha, interleukin-6 and tumour necrosis factor alpha were released within 3-6
h, while interleukin-8, gamma interferon and granulocyte-macrophage colony
stimulating factor were released after 18 h. Interleukin-3 and interleukin-4
were not detected at up to 48 h of incubation. In conclusion, these
immunomodulating and histotropic properties may account for Y. enterocolitica
infection and its sequelae.

14. J Immunol 1997 Feb 15;158(4):1976-83 
Lipoprotein from Yersinia enterocolitica contains epitopes that cross-react
with the human thyrotropin receptor.
Zhang H, Kaur I, Niesel DW, Seetharamaiah GS, Peterson JW, Prabhakar BS,
Klimpel GR
Department of Microbiology and Immunology, University of Texas Medical Branch,
Galveston 77555, USA.

Yersinia enterocolitica has recently been shown to produce a low molecular mass
envelope protein that contains an epitope(s) that is cross-reactive with the
extracellular domain of the human thyrotropin receptor (ETSHR). In this study,
we have generated mAb to this cross-reactive protein and have obtained amino
acid sequences for peptide fragments obtained from Lys-c digestion of the
protein. The amino acid sequences of these peptides were identical to sequences
present in bacterial lipoprotein (LP). All bacteria of the Enterobacteriaceae
family produce LP as a major outer membrane protein. However, the ETSHR
cross-reactive epitope(s) was shown to be unique to LP produced by Yersinia
species. This was shown by Western blot analysis using a mAb specific for LP
and with affinity-purified Ab specific for either LP or ETSHR and obtained from
mouse antiserum generated to Y. enterocolitica. LPs from different
Gram-negative bacteria were shown to be mitogenic for C3H/HeJ spleen cells and
induced production and secretion of significant levels of Ig. Production of Ab
that recognized the ETSHR was only induced in spleen cells stimulated with the
LP obtained from Yersinia. In contrast, LP was not mitogenic for either human
PBMC or human B cells. However, LP did induce IL6 and IL8 production in human
monocytes at levels equivalent to that seen after LPS activation. These results
identify, for the first time, the Yersinia envelope protein that is
cross-reactive with the ETSHR and show that it can activate human monocytes.
These findings are potentially important for advancing our understanding of the
role molecular mimicry plays in the induction of autoimmunity to the
thyrotropin receptor.


15. Infect Immun 1997 Jun;65(6):2060-6 
Yersinia enterocolitica serotype O:3 alters the expression of serologic HLA-B27
epitopes on human monocytes.
Wuorela M, Jalkanen S, Kirveskari J, Laitio P, Granfors K
Department in Turku, National Public Health Institute, University of Turku,
Finland. 

The expression of serologic HLA-B27 epitopes on leukocytes of patients with
reactive arthritis or ankylosing spondylitis has been shown to be modified in
the course of the disease. The purpose of this work was to study whether
phagocytosis of arthritis-triggering microbes in vitro alters the expression of
HLA-B27 molecules on human antigen-presenting cells and to characterize the
underlying mechanisms. Human monocytes and HLA-B27- or HLA-A2-transfected human
U-937 cells were exposed to Yersinia enterocolitica serotype O:3. The
expression of different epitopes of HLA-B27 was monitored by using
immunofluorescence, and their synthesis was determined by quantitative
immunoprecipitation. Our results show that phagocytosis of Y. enterocolitica
serotype O:3 changed the expression of serological HLA-B27 epitopes. This was
due to the reduced synthesis of HLA-B27 molecules. The expression of especially
the epitopes which depend on the presence of peptides in the antigen-binding
groove was changed. The expression of the ME1 epitope, which has been shown to
be important for T-cell recognition in patients with reactive arthritis, was
decreased. Down-regulation of epitopes important for the T-cell recognition may
impair the elimination of arthritis-triggering microbes and lead to persistent
infection. In addition, Y. enterocolitica serotype O:3 seemed to alter the
repertoire of peptides presented by the HLA-B27 molecules on human monocytes.
This may have a role in the pathogenesis of reactive arthritis via an
autoimmune mechanism.

16. Arthritis Rheum 1997 Apr;40(4):694-703 
Induction of alternative splicing of HLA-B27 by bacterial invasion.
Huang F, Yamaguchi A, Tsuchiya N, Ikawa T, Tamura N, Virtala MM, Granfors K,
Yasaei P, Yu DT
University of California Los Angeles, 90095-167022, USA.

OBJECTIVE: Alternative splicing of certain class I major histocompatibility
complex pre-messenger RNA (pre-mRNA) is known to lead to generation of a
cell-free soluble protein analog. This study was undertaken to examine whether
this process occurs with HLA-B27, whether the process is modified by
arthritis-causing bacteria, and whether the assembly of the soluble molecules
follows the same pathway as the integral parent molecules. METHODS: Alternative
splicing of pre-mRNA was analyzed by reverse transcriptase-polymerase chain
reaction, and assembly of soluble HLA-B27 by immunoprecipitation followed by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography.
RESULTS: There was alternative splicing of the pre-mRNA of HLA-B27. The process
could be amplified by invasion with Salmonella or Yersinia bacteria. The
soluble HLA-B27 was assembled in a pathway similar to that of the parent
molecule. CONCLUSION: The association between arthritis-causing bacteria and
HLA-B27 positive cells is a complex event. Soluble HLA-B27 is a potential key
player.

17. Blood 1994 May 15;83(10):2836-43 
Differential regulation of stem cell factor mRNA expression in human
endothelial cells by bacterial pathogens: an in vitro model of inflammation.
Koenig A, Yakisan E, Reuter M, Huang M, Sykora KW, Corbacioglu S, Welte K
Department of Pediatric Hematology and Oncology, Children's Hospital, Medical
School Hannover, Germany.

Production of hematopoietic growth factors by endothelial cells plays a pivotal
role during inflammatory processes. Stem cell factor (SCF) is known to be
expressed constitutively in endothelial cells. To investigate the regulation of
this cytokine expression by inflammatory stimuli, we cocultured human umbilical
vein endothelial cells (HUVEC) with various gram-negative bacterial strains
(Escherichia coli, Yersinia enterocolitica, Chlamydia trachomatis, and
Neisseria meningitidis, respectively). Experiments were performed with
bacterial concentrations ranging from 10(2) to 10(7) bacteria/mL for 3 hours.
SCF-specific mRNA expression was studied using Northern blot analysis.
Stimulation with the enteropathogenic bacterial strains Y enterocolitica and E
coli resulted in a significant concentration-dependent increase of SCF mRNA
expression. Similar results were obtained in coculture experiments with N
meningitidis. As shown in experiments with E coli, the accumulation of SCF
transcripts was also time-dependent. In contrast, coculture of HUVEC with the
intracellular gram-negative strain C trachomatis had no effect on SCF mRNA
expression. To elucidate the role of the gram-negative bacterial cell wall
components, we stimulated HUVEC with bacterial lipopolysaccharide (LPS). LPS
induced a maximal SCF mRNA accumulation within 2 hours followed by decrease of
SCF-specific transcripts to the basal level after 24 hours. In addition, we
exposed HUVEC to the classical inflammatory cytokine interleukin-1 alpha (IL-1
alpha). Kinetic experiments showed a similar pattern of regulation with an
increase of SCF mRNA within 2 hours, persisting up to 12 hours, and a decrease
to basal transcription after 24 hours. From these data, we conclude that SCF
expression is regulated by inflammatory stimuli, such as IL-1 alpha and
bacterial pathogens, suggesting an important role of SCF during inflammation.
PMID: 7514047, UI: 94235848

17b. Infect Immun 1999 Feb;67(2):726-32 
Monocytes that have ingested Yersinia enterocolitica serotype O:3 acquire
enhanced capacity to bind to nonstimulated vascular endothelial cells via
-selectin.
Wuorela M, Tohka S, Granfors K, Jalkanen S
National Public Health Institute, University of Turku, Turku, Finland.

...The data presented here show that mononuclear phagocytes which mediate the
dissemination of several intracellular pathogens acquire an enhanced capacity
to bind to nonstimulated vascular endothelial cells after phagocytosis of
Yersinia enterocolitica O:3... The increased binding to previously nonstimulated
endothelial cells was mediated by P-selectin, whose translocation to the
endothelial cell surface was induced by monocytes with intracellular Yersinia
bacteria. These results suggest that mononuclear phagocytes may be responsible
for the dissemination of bacterial antigens... 

18. Radiologe 1998 Jan;38(1):37-40 
[Mesenteric lymphadenopathy in Yersinia enterocolitica infection].
[Article in German]
Trommer G, Bewer A, Kosling S
Klinik und Poliklinik fur Diagnostische Radiologie der Universitat Leipzig.

We report a case of previously undiagnosed Yersinia enterocolitica infection in
a 46-year old woman. She consulted her physician because of continual weight
loss and physical lassitude. A leucocytosis was found. Sonography revealed an
excessive enlargement of abdominal lymph nodes. A malignant lymphoma was
suspected and the patient underwent a staging by CT. There the disease was
limited on mesenteric and retroperitoneal lymph nodes. Bone marrow biopsy and
CT-guided lymph node biopsy did not confirm a systemic lymphatic disease. The
patient did not undergo a special therapy. After six months, CT showed a clear
regression of enlarged lymph nodes. Finally, a previous Yersinia enterocolitica
infection of immunotype 03 could be proved serologically. At this time, the
patient had no complaints. Diagnostic and differential diagnosis of benign
abdominal lymph node enlargement are discussed based on literature.
PMID: 9530777, UI: 98191910

19a. Hematol Oncol Clin North Am 1993 Aug;7(4):865-85 
Approach to management of fever and infection in patients with primary bone
marrow failure and hemoglobinopathies.
Weinberger M
Department of Clinical Microbiology and Infectious Diseases, Hadassah Medical
Center, Jerusalem, Israel.

The characteristic spectrum of infections in patients with aplastic anemia,
chronic neutropenic diseases, sickle cell disease, thalassemia, and other
hemoglobinopathies are described. The major risk factor for infection in
patients with bone marrow failure is the degree of neutropenia and
monocytopenia. In patients with aplastic anemia, invasive fungal infections
emerge as the major causes of mortality. Life-threatening infections are rare
in patients with chronic neutropenic diseases; however, necrotizing
enterocolitis due to Clostridium species may be an exception. Bacterial
infections, predominantly with encapsulated bacteria, are the most common cause
of death in patients with sickle cell disease, especially those who are younger
than 5 years of age. Patients with thalassemia and other hemoglobinopathies are
particularly susceptible to life-threatening infections with Yersinia
enterocolitica as a result of iron overload or of the chelating therapy with
desferrioxamine.

19b. Clin Infect Dis 1998 Jul;27(1):59-64 
Surveillance of human Yersinia enterocolitica infections in Belgium: 1967-1996.
Verhaegen J et al.
Department of Medical Microbiology, University Hospitals, Leuven, Belgium.
     ab: Between 1967 and 1996, > 18,700 strains of Yersinia species, excluding
Yersinia pestis, were recovered in Belgium from a variety of gastrointestinal
and extraintestinal sites in patients...

20. Dig Dis Sci 1998 Jun;43(6):1341-6 
Collagenous colitis and Yersinia enterocolitica infection.
Makinen M, Niemela S, Lehtola J, Karttunen TJ
Department of Pathology, University of Oulu, Finland.

Collagenous colitis is a rare clinical and pathological entity characterized by
watery diarrhea and deposition of collagen beneath the surface epithelium of
the colon. Its etiology is unknown. We present a careful retrospective
clinicopathological analysis of six patients with collagenous colitis diagnosed
at our hospital during a three-year period. Three of the patients had had a
Yersinia enterocolitica infection, detected by stool culture and elevated serum
antibody titers, preceding the diagnosis of collagenous colitis. Four patients
had duodenal villous atrophy, which in two patients was refractory to a
gluten-free diet. We propose that Yersinia enterocolitica infection may be a
triggering factor for the development of collagenous colitis in some cases.
Duodenal villous atrophy not responding to gluten withdrawal is common in
association with collagenous colitis.
PMID: 9635629, UI: 98297552

21.  Infect Immun 1998 Mar;66(3):1113-20 
Identification of virulence-associated characteristics in clinical isolates of
Yersinia enterocolitica lacking classical virulence markers.
Grant T et al.

Yersinia enterocolitica is an important enteric pathogen which has well-defined
virulence determinants that allow the bacteria to become established in their
hosts and overcome host defenses. A number of strains obtained from patients
with diarrhea, however, lack these genes. Accordingly, the mechanisms by which
they cause disease are uncertain. Most of these isolates belong to biotype 1A.
Strains of this biotype are also frequently isolated from a variety of
nonclinical sources, such as food, soil, water, and healthy animals, and there
is evidence that some of these strains are avirulent. In this study we
investigated 111 strains of Y. enterocolitica biotype 1A, 79 from symptomatic
humans and 32 from nonclinical sources, for virulence-associated
characteristics... These results indicate that some clinical isolates of Y.
enterocolitica which lack classical virulence markers may be able to cause
disease via virulence mechanisms which differ from those previously
characterized in enteropathogenic Yersinia species.

22. Scand J Infect Dis 1996;28(6):571-5 
Clinical presentation and diagnosis of gastrointestinal infections by Yersinia
enterocolitica in 261 Dutch patients.
Stolk-Engelaar VM, Hoogkamp-Korstanje JA
Department of Medical Microbiology, University Hospital Nijmegen, The
Netherlands.

A surveillance of the clinical manifestations, course and outcome of 261
patients with gastrointestinal infection by Yersinia enterocolitica between
1982 and 1991 was carried out. Acute uncomplicated enteritis was diagnosed in
169 patients, complicated enteritis in 37, appendicular syndrome in 33, ileitis
in 8 and colitis in 14. Children (age < 16 years, n = 105) presented most often
with mild enteritis, young adults (age 16-25 years, n = 47) with enteritis or
appendicular syndrome, adults (age > 25 years, n = 109) had significant risk
for developing serious enteritis, ileitis and colitis. Complications included
reactive arthritis, septicaemia, lymphadenitis, disturbed liver functions and
erythema nodosum. Four patients died of generalized peritonitis. Diagnosis was
established by positive culture in 207 patients. Another 54 patients were
diagnosed by having at least two other positive tests: serum agglutinins,
specific IgA and IgG antibodies to Yersinia outer membrane proteins (Yops) or
antigen detection in biopsies. Culture alone was sufficient to diagnose
uncomplicated enteritis, antiYops serology appeared to be very useful in
diagnosing patients with other manifestations of yersiniosis. The majority of
the infections were caused by serotypes O3 and O9 while unusual serotypes were
associated with advancing age and colitis.

23.  I shall attempt to verify with Great Smokies that their microbiology panel
does not identify gastrointestinal Yersinia enterocolitica. Another possibility,
for Mike, is that his anti-Yersinia-enterocolitica antibodies were directed
against lingering Y.e. lipopolysaccharide particles and/or that if he has a
chronic Yersinia infection, its location is outside the intestine.

24.  Infect Control Hosp Epidemiol 1992 Mar;13(3):139-43 
Yersinia enterocolitica infections in hospitalized patients: the problem of
hospital-acquired infections.
Cannon CG, Linnemann CC Jr
Infection Control Department, University of Cincinnati Hospital, OH 45267-0788.

OBJECTIVE: To study the epidemiology of Yersinia enterocolitica infections in
hospitalized patients and to determine the frequency of hospital-acquired
infection and the modes of transmission within the hospital. DESIGN:
Descriptive study in which the clinical microbiology laboratory reported all
positive Yersinia cultures to the infection control department; each case was
investigated to determine the source of infection. SETTING: A 700-bed
university teaching hospital. PARTICIPANTS: All patients who were
culture-positive for Y enterocolitica after admission to the University of
Cincinnati Hospital during the 4-year period between 1987 and 1990. RESULTS: Of
18 patients who were diagnosed with Yersinia infections, 8 (44%) were
community-acquired. These patients were admitted with gastrointestinal symptoms
and had their first positive cultures between days 1 and 5 of their
hospitalizations. Five patients (28%) had hospital-acquired infections, having
developed diarrhea after admission for unrelated problems, and became
culture-positive between days 18 and 66. The remaining 5 patients could not be
classified as either community- or hospital-acquired. These patients had
gastrointestinal symptoms at the time of admission, but these could have been
explained by other diseases. Their first positive stool cultures were not
obtained until the second week or later during hospitalization, and 3 of these
patients had negative stool cultures prior to a positive culture. CONCLUSIONS:
Although Y enterocolitica has not previously been recognized as a common
hospital problem, at least 28% of our patients acquired their Yersinia
infections in the hospital. In some cases, cross infections, transmitted by
healthcare workers, occurred between patients. Four of the 18 infections
occurred in patients with acquired immunodeficiency syndrome.
Comments:  Comment in: Infect Control Hosp Epidemiol 1992 Mar;13(3):137-8

25. Emily Yoffe, Science Section of The New York Times, Noverber 9, 1999.
Comment: This is an important article, well worth the $1 or $2 that may be
charged to someone wanting to download the article from
NY Times Science
26. J Immunol 1999 Apr 15;162(8):4806-16 
Human cytomegalovirus binding to human monocytes induces immunoregulatory gene
expression.
Yurochko AD, Huang ES
Lineberger Comprehensive Cancer Center, Department of Medicine, University of
North Carolina, Chapel Hill 27599 USA

To continue our investigation of the cellular events that occur following human
CMV (HCMV) infection, we focused on the regulation of cellular activation
following viral binding to human monocytes... 
These results support our hypothesis that HCMV initiates a signal transduction
pathway that leads to monocyte activation and pinpoints a potential mechanism
whereby HCMV infection of monocytes can result in profound pathogenesis,
especially in chronic inflammatory-type conditions.

27. Circ Res 1997 Jul;81(1):8-16 
Monocytes harboring cytomegalovirus: interactions with endothelial cells,
smooth muscle cells, and oxidized low-density lipoprotein. Possible mechanisms
for activating virus delivered by monocytes to sites of vascular injury.
Guetta E, Guetta V, Shibutani T, Epstein SE
Department of Cell Biology, Cleveland Clinic Foundation, OH 44195, USA.

28. Pathol Biol (Paris) 1997 Feb;45(2):146-58 
Interaction of human cytomegalovirus with monocytes/macrophages: a love-hate
relationship.
Michelson S
Unite d'Immunologie Virale, Institut Pasteur, Paris, France.

29. APMIS 1997 Feb;105(2):89-98 
The effect of human cytomegalovirus on selected functions of peripheral blood
monocytes.
Holberg-Petersen M, Rollag H, Beck S, Degre M
Kaptein W. Wilhelmsen og Frues Institute of Microbiology, Rikshospitalet, Oslo,
Norway.

The effect of in vitro infection of human cytomegalovirus (HCMV) on various
monocyte functions relevant to antimicrobial defence mechanisms has been
investigated: the phagocytic activity of monocytes, the release of lysozyme and
intracellular concentration of acid phosphatase, and the release of the
cytokines interleukin-1 (IL-1), IL-6, and tumour necrosis factor-alpha
(TNF-alpha). HCMV significantly inhibited the release of lysozyme and
intracellular concentration of acid phosphatase. Regarding the phagocytic
activity and the release of cytokines, there was considerable variation in the
HCMV effect among the different blood donors tested. There was no clear
tendency in the observed results; both stimulation and inhibition were seen.
The HCMV-specific pp65 was detected in the nucleus of about 1% of the monocytes
3 h after infection and HCMV-specific IE antigens were found in about 0.1% of
the monocytes 2 days postinfection. No E- or L-gene expression was observed and
no infectious virus was produced in the monocytes. Our results indicate that
HCMV infection may influence monocyte functions in spite of no productive
infection of these cells.

30. Virology 1996 Sep 1;223(1):198-207 
Murine cytomegalovirus DNA in peripheral blood of latently infected mice is
detectable only in monocytes and polymorphonuclear leukocytes.
Mitchell BM, Leung A, Stevens JG

31. J Clin Invest 1996 Jun 1;97(11):2635-41 
Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis
factor-dependent release of arachidonic acid and prostaglandin E2 in human
monocytes.
Nokta MA, Hassan MI, Loesch K, Pollard RB

32. J Infect Dis 1995 Feb;171(2):263-72 
Bidirectional transmission of infectious cytomegalovirus between monocytes and
vascular endothelial cells: an in vitro model.
Waldman WJ, Knight DA, Huang EH, Sedmak DD

33. J Virol 1994 Mar;68(3):1597-604 
Induction of endogenous human cytomegalovirus gene expression after
differentiation of monocytes from healthy carriers.
Taylor-Wiedeman J, Sissons P, Sinclair J
Department of Medicine, University of Cambridge, United Kingdom.

Monocytes are one site of carriage of the human cytomegalovirus (HCMV) genome
in healthy human carriers. However, as there are conflicting data detailing the
level of HCMV gene expression during persistence in these cells, we have
analyzed monocytes for evidence of viral immediate-early, early, and late
transcription by using reverse transcription followed by PCR. We were unable to
find evidence of HCMV lytic gene transcription in freshly isolated peripheral
blood monocytes from HCMV-seropositive subjects. However, as differentiation of
monocytes to monocyte-derived macrophages results in increased permissiveness
to infection with HCMV in vitro, we examined whether such differentiation could
result in reactivation of endogenous viral gene expression. Here we show that
in vitro differentiation of monocytes does result in expression of endogenous
HCMV immediate-early genes. Although this differentiation led to reactivation
of endogenous viral immediate-early expression, we were unable to detect any
early or late viral transcription. Cocultivation experiments correlated with
this level of gene induction, as no productive infection was detected. These
data strongly suggest a mechanism of persistence of HCMV in the peripheral
blood that is independent of HCMV lytic gene expression and that initial phases
of lytic gene expression in monocytes can be induced by differentiation of
these cells to monocyte-derived macrophages. 
PMID: 8107221, UI: 94149850

34. Virus Res 1993 Jul;29(1):79-90 
Human herpesvirus 6 (HHV-6)-associated dysfunction of blood monocytes.
Burd EM, Carrigan DR
Department of Pathology, Medical College of Wisconsin, Milwaukee 53226.

...These findings suggest that HHV-6 infection may be associated with a defect
in one of the major monocyte activation pathways, and this could be of
importance with respect to persistent infection by HHV-6 in immune compromised
patients.

35. J Clin Invest 1992 Nov;90(5):1642-8 
Cytomegalovirus induction of tumor necrosis factor-alpha by human monocytes and
mucosal macrophages.
Smith PD, Saini SS, Raffeld M, Manischewitz JF, Wahl SM
Cellular Immunology Section, National Institute of Dental Research, National
Institutes of Health, Bethesda, Maryland 20892.

Cytomegalovirus (CMV) is a major cause of inflammatory organ disease in
immunosuppressed persons. To elucidate the mechanisms of CMV-induced
inflammation, we investigated whether tumor necrosis factor-alpha (TNF-alpha)
was involved in the pathogenesis of CMV colitis in patients with AIDS. In in
situ hybridization experiments, TNF-alpha mRNA was shown to be abundantly
present in colonic mucosa from AIDS patients with CMV colitis but not in
colonic mucosa from control (AIDS and normal) subjects. The TNF-alpha
transcripts, identified in macrophage-like cells containing cytomegalic
inclusions, were positively associated with CMV, but not HIV-1, within the
mucosa. In in vitro experiments, a patient-derived isolate of CMV, but not
HIV-1Ba-L, induced human monocytes to express TNF-alpha mRNA and to release
increased levels of TNF-alpha peptide following stimulation. CMV induction of
TNF-alpha may play a critical role in CMV-induced inflammation...

36. J Gen Virol 1991 Sep;72 ( Pt 9):2059-64 
Monocytes are a major site of persistence of human cytomegalovirus in
peripheral blood mononuclear cells. 
              [and antibodies against CMV may not be present!]
Taylor-Wiedeman J, Sissons JG, Borysiewicz LK, Sinclair JH

We have used the nested polymerase chain reaction (PCR) combined with
fluorescence-activated cell sorting to define sites of latency of human
cytomegalovirus (HCMV) in the peripheral blood of healthy subjects. Peripheral
blood mononuclear (PBM) cells were separated into T cell or non-T cell
populations and monocytes, and were then analysed by PCR for the presence of
HCMV DNA. In five of six seropositive subjects, HCMV was found predominantly in
the non-T cell population. Further analysis suggested that the virus was
present in adherent cells and CD14+ cells. In three of nine seronegative
subjects we could demonstrate HCMV DNA, which we do not believe was due to
contamination, reproducibly by PCR. In one of these seronegative subjects, HCMV
DNA was present predominantly in the non-T cell fraction of PBM cells. No HCMV
DNA was detectable in the remaining six seronegative subjects. We conclude
that, within the PBM cells of normal asymptomatic seropositive and some
seronegative subjects, HCMV is present predominantly in the monocyte fraction.
In addition, the detection of HCMV sequences in seronegative subjects may
indicate that infection with HCMV is more widespread than conventional
seroepidemiology suggests.

37. J Gen Virol 1991 Jun;72 ( Pt 6):1401-8 
Latent human herpesvirus 6 infection of human monocytes/macrophages.
Kondo K, Kondo T, Okuno T, Takahashi M, Yamanishi K
Department of Virology, Osaka University, Japan.

...Therefore, we have developed an in vitro latency system for HHV-6; our
results suggest that HHV-6 may latently infect monocytes in vivo and in vitro
and that it may be reactivated in cells by some factors.

38. Leuk Lymphoma 1999 Mar;33(1-2):1-13 
Human cytomegalovirus infection of human hematopoietic progenitor cells.
Maciejewski JP, St Jeor SC
Department of Microbiology, University of Nevada, Medical School, Reno 89503,
USA.

For a number of years it has been well established that human cytomegalovirus
(HCMV) can be transmitted by the cellular components of blood. HCMV is also
associated with a number of hematologic disorders. Although HCMV was thought to
be present in blood cells in a latent or persistent form, it was not known how
the virus was maintained and which cells were the carriers of HCMV. In addition
to peripheral blood cells, there has been clinical evidence that HCMV may be
associated with specific disorders of the hematopoietic system. Recently, a
number of advances in cell and molecular biology have helped to develop a
better understanding of the relationship between HCMV and the hematopoietic
system. The application of the polymerase chain reaction (PCR) to the study of
HCMV infection has revealed that the virus was present in mononuclear cells
with only limited transcription of its genome. Studies conducted in our
laboratory have demonstrated that both CD34+ progenitor cells and monocytes
could be infected with HCMV and virus recovered when the cells were allowed to
terminally differentiate. Subsequently, these results have been confirmed in
vivo: HCMV DNA and limited RNA transcripts could be detected in in vivo
infected hematopoietic progenitor cells and HCMV has been rescued from
macrophages derived through in vitro differentiation of monocytes from normal
seropositive blood donors. Although our understanding of the relationship
between HCMV and the hematopoietic system has been advanced, the mechanisms by
which the virus can be maintained in a latent state and how it is reactivated
is still unclear. Furthermore, it remains to be determined what HCMV-mediated
effect is responsible for the inhibition of hematopoiesis following an in vitro
infection and its significance in vivo.

39. Virology 1999 Jan 20;253(2):145-54 
In vivo disturbance of hematopoiesis in mice persistently infected with murine
cytomegalovirus: impairment of stromal cell function.
Mori T, Nakamura M, Shimizu K, Ikeda Y, Ando K

Although the pathogenic effects of a primary cytomegalovirus (CMV) infection on
hematopoiesis has been largely investigated so far, the effects of a persistent
or latent infection have yet to be elucidated...  These results therefore
strongly suggest that MCMV remains to infect the stromal cells while also
inhibiting inductive hematopoiesis through the impairment of the stromal cell
functions in the MCMV persistently infected mice. Copyright 1999 Academic
Press.

40. Int J Hematol 1998 Jan;67(1):91-3 
Hematopoietic suppression in a child with human herpesvirus-6 infection.
Sugita K, Hagisawa S, Eguchi M, Furukawa T

41. Blood 1997 Sep 15;90(6):2482-91 
Spread of human cytomegalovirus (HCMV) after infection of human hematopoietic
progenitor cells: model of HCMV latency.
Zhuravskaya T, Maciejewski JP, Netski DM, Bruening E, Mackintosh FR, St Jeor S

Clinical experience and laboratory data suggest that human cytomegalovirus
(HCMV) is present in peripheral blood of seropositive individuals in a latent
or persistent state and can be transmitted via blood products and be
reactivated in seropositive immunocompromised patients...
Proliferation and monocytic maturation of infected progenitors may lead to the
numerical expansion of HCMV-infected cells, which serve as a source of HCMV
dissemination and reactivation.

42. J Med Virol 1997 Aug;52(4):406-12 
Suppressive effects of human herpesvirus 6 on in vitro colony formation of
hematopoietic progenitor cells.
Isomura H, Yamada M, Yoshida M, Tanaka H, Kitamura T, Oda M, Nii S, Seino Y
Department of Pediatrics, Okayama University Medical School, Shikatacho, Japan.

Human herpesvirus 6 (HHV-6) has been reported to be involved in bone marrow
failure after bone marrow transplantation (BMT). To elucidate the role of HHV-6
in the marrow failure, we examined the comparative effect of two variants of
HHV-6 (HHV-6A and HHV-6B) and human herpesvirus 7 (HHV-7) on in vitro colony
formation of hematopoietic progenitor cells...  Based on frequent positivity of
viral DNA in single colonies obtained from HHV-6-infected progenitor cells by
polymerase chain reaction and in situ hybridization, direct effects of HHV-6 on
the hematopoietic progenitor cells are suggested as the cause of the suppression
rather than indirect effects via accessory cells of the bone marrow.

43. J Clin Microbiol 1998 Sep;36(9):2557-64 
Development of rRNA-targeted PCR and in situ hybridization with fluorescently
labelled oligonucleotides for detection of Yersinia species.
Trebesius K, Harmsen D, Rakin A, Schmelz J, Heesemann J

44. Mol Cell Probes 1998 Apr;12(2):79-83 
A simplified sample preparation method from various foods for PCR detection of
pathogenic Yersinia enterocolitica: a possible model for other food pathogens.
Bhaduri S, Cottrell B

45. J Clin Microbiol 1997 Jun;35(6):1636-8 
Development of a highly specific assay for rapid identification of pathogenic
strains of Yersinia enterocolitica based on PCR amplification of the Yersinia
heat-stable enterotoxin gene (yst).
Ibrahim A, Liesack W, Griffiths MW, Robins-Browne RM

46. Epidemiol Infect 1996 Aug;117(1):59-67 
Detection of pathogenic Yersinia enterocolitica using the multiplex polymerase
chain reaction.
Harnett N, Lin YP, Krishnan C


Yersinia cross-reactivities and
thyroid-
related autoimmunity
A series of autism-related webpagesContents
email to: Teresa
Binstock

copyright 1999