Cryptosporidiosis Facilitated by Murine Retroviral Infection with LP-BM5

Darban, Hamid; Enríquez, José Antonio; Sterling, Charles R.; López, Marı́a C.; Chen, G.; Abbaszadegan, Morteza; Watson, Ronald R.

doi:10.1093/infdis/164.4.741

Cited by 42 publications

(12 citation statements)

References 24 publications

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“…Previous studies have shown that a lack of coordinated responses from CD8 + T-cells and natural killer cells facilitated HSV-1 spread into brains of C57BL/6 mice [31]. MAIDS models have been extensively used to understand the pathogenesis of opportunistic infections [18,20,21,32]. In our model of LP-BM5-induced immunodeficiency, otherwise resistant C57BL/6 mice became sensitive to opportunistic brain infection.…”

Section: Discussionmentioning

confidence: 93%

“…It has been postulated that this Th1 to Th2 shift is required for progression to MAIDS. Furthermore, this retroviral infection increases susceptibility to other infections and has been used to study opportunistic parasites and fungi [19-21]. Normal C57BL/6 mice have been shown to be resistant to HSV-1 encephalitis when inoculated through the i.n.…”

Section: Resultsmentioning

confidence: 99%

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T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection

Mutnal

Schachtele

et al. 2013

J Neuroinflammation

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BackgroundHighly active antiretroviral therapy (HAART) restores inflammatory immune responses in AIDS patients which may unmask previous subclinical infections or paradoxically exacerbate symptoms of opportunistic infections. In resource-poor settings, 25% of patients receiving HAART may develop CNS-related immune reconstitution inflammatory syndrome (IRIS). Here we describe a reliable mouse model to study underlying immunopathological mechanisms of CNS-IRIS.MethodsUtilizing our HSV brain infection model and mice with MAIDS, we investigated the effect of immune reconstitution on MAIDS mice harboring opportunistic viral brain infection. Using multi-color flow cytometry, we quantitatively measured the cellular infiltrate and microglial activation.ResultsInfection with the LP-BM5 retroviral mixture was found to confer susceptibility to herpes simplex virus (HSV)-1 brain infection to normally-resistant C57BL/6 mice. Increased susceptibility to brain infection was due to severe immunodeficiency at 8 wks p.i. and a marked increase in programmed death-1 (PD-1) expression on CD4+ and CD8+ T-cells. Both T-cell loss and opportunistic brain infection were associated with high level PD-1 expression because PD-1-knockout mice infected with LP-BM5 did not exhibit lymphopenia and retained resistance to HSV-1. In addition, HSV-infection of MAIDS mice stimulated peripheral immune cell infiltration into the brain and its ensuing microglial activation. Interestingly, while opportunistic herpes virus brain infection of C57BL/6 MAIDS mice was not itself lethal, when T-cell immunity was reconstituted through adoptive transfer of virus-specific CD3+ T-cells, it resulted in significant mortality among recipients. This immune reconstitution-induced mortality was associated with exacerbated neuroinflammation, as determined by MHC class II expression on resident microglia and elevated levels of Th1 cytokines in the brain.ConclusionsTaken together, these results indicate development of an immune reconstitution disease within the central nervous system (CNS-IRD). Experimental immune reconstitution disease of the CNS using T-cell repopulation of lymphopenic murine hosts harboring opportunistic brain infections may help elucidate neuroimmunoregulatory networks that produce CNS-IRIS in patients initiating HAART.

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection

Mutnal

Schachtele

et al. 2013

J Neuroinflammation

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“…Prior infection of C57BV6 mice with LP-BMS MuLVs did not affect the kinetics of C. neoformans infection, as fungal counts in the lungs and brain remained similar in LP-BMS-infected and MuLV induces profound immunodeficiency. It has been shown that the immune defects occurring during this retroviral disease increase susceptibility to various pathogens [ 16, including a fungus. Cole et al reported increased susceptibility to gastrointestinal candidiasis after LP-BMS-induced immunosuppression [17].…”

Section: Discussionmentioning

confidence: 99%

Cryptococcus neoformans infection in mice previously infected with LP-BM5 MuLV, the agent of murine AIDS (MAIDS)

Lacroix

Chau

Carbon

et al. 1997

Clinical and Experimental Immunology

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SUMMARYWe studied susceptibility to experimental systemic cryptococcosis in mice previously infected with the retroviral complex LP-BMS (responsible for murine AIDS). LP-BMS was inoculated to C57BV6 mice by intravenous (i.v.) injection 8 weeks before an i.v. challenge with 4 x lo3 CFU of Cryptococcus neoforrnans. Uninfected and singly infected mice were used as controls. LP-BMS infection did not result in a significant increase in fungal burdens in the lungs or brains of co-infected animals compared to mice infected with C. neoformans alone. However, mortality was enhanced in the co-infected animals. The kinetics of splenocyte subsets differed in co-infected mice and LP-BMS-infected mice; the increase in CD4+, CD8+ and LyS+ cells was only moderate in the former. Cytokine production by concanavalin A (Con A)-stimulated splenocytes from co-infected mice showed a marked decrease in the Thl response (IFN-y, IL-2) and an increase in the Th2 response (IL-4, IL-10). Furthermore, cryptococcosis altered the course of MAIDS, inhibiting splenomegaly. This effect was not related to a decrease in ecotropic virus titres in the spleen or to improved in v i~o responsiveness of spleen cells to Con A. The marked decrease in IFN-y production in co-infected animals could partly explain the inhibition of LP-BMS-induced splenomegaly. This model of murine retroviral infection does not seem to be suitable for studying cryptococcosis in immunosuppressed animals, but remains valuable for investigating in vivo interactions between two pathogens.

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“…The finding that retrovirus-infected mice could become infected with Cryptosporidium parvum a gut parasite, was a starting point for an interest in how LP-BM5 infection was altering gut mucosal immunity (Darban et al 1991). Further studies clearly indicated that while mesenteric lymph nodes (MLN) increased in size and cell numbers the opposite was the case for Peyer's patches and the gut lamina propria (Lopez et al 1992c).…”

Section: Introductionmentioning

confidence: 99%

Alterations in Mesenteric Lymph Node T Cell Phenotype and Cytokine Secretion are Associated with Changes in Thymocyte Phenotype after LP‐BM5 Retrovirus Infection

López

Watson

2005

Journal of Immunology Research

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In this study, mouse MLN cells and thymocytes from advanced stages of LP-BM5 retrovirus infection were studied. A decrease in the percentage of IL-7 þ cells and an increase in the percentage of IL-16 þ cells in the MLN indicated that secretion of these cytokines was also altered after LP-BM5 infection. The percentage of MLN T cells expressing IL-7 receptors was significantly reduced, while the percentage of MLN T cells expressing TNFR-p75 and of B cells expressing TNFR-p55 increased. Simultaneous analysis of surface markers and cytokine secretion was done in an attempt to understand whether the deregulation of IFN-g secretion could be ascribed to a defined cell phenotype, concluding that all T cell subsets studied increased IFN-g secretion after retrovirus infection. Finally, thymocyte phenotype was further analyzed trying to correlate changes in thymocyte phenotype with MLN cell phenotype. The results indicated that the increase in single positive either CD4 þ CD8 2 or CD4 2 CD8 þ cells was due to accumulation of both immature (CD3 2 ) and mature (CD3 þ ) single positive thymocytes. Moreover, single positive mature thymocytes presented a phenotype similar to the phenotype previously seen on MLN T cells. In summary, we can conclude that LP-BM5 uses the immune system to reach the thymus where it interferes with the generation of functionally mature T cells, favoring the development of T cells with an abnormal phenotype. These new T cells are activated to secrete several cytokines that in turn will favor retrovirus replication and inhibit any attempt of the immune system to control infection.

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Cryptosporidiosis Facilitated by Murine Retroviral Infection with LP-BM5

Cited by 42 publications

References 24 publications

T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection

T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection

Cryptococcus neoformans infection in mice previously infected with LP-BM5 MuLV, the agent of murine AIDS (MAIDS)

Alterations in Mesenteric Lymph Node T Cell Phenotype and Cytokine Secretion are Associated with Changes in Thymocyte Phenotype after LP‐BM5 Retrovirus Infection

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