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Mechanisms of Measles Virus-Induced Immune Suppression in the Cotton Rat Model

Carsillo, Mary Elizabeth
http://rave.ohiolink.edu/etdc/view?acc_num=osu1249584349

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
The World Health Organization estimates that approximately 200,000 people, the majority of them children, died in 2007 following acute measles. Bacterial pneumonia following virus-induced immune suppression is one of the leading fatal complications of acute Measles virus (MV) infection. Despite its clinical importance, the underlying mechanisms of MV-induced immunosuppression remain unresolved. To study MV-induced immune suppression we use the cotton rat, because it is the only rodent shown to replicate MV in the respiratory tract after intranasal infection and to develop T-cell proliferation inhibition, a hallmark of MV-induced immune suppression. Enhanced pulmonary susceptibility to secondary bacterial infection in MV-infected patients is well established. This might indicate a defect in the macrophage response, as these cells play an important role in immune responses against bacterial infections through phagocytosis and microbicidal activity as well as through cytokine production and the stimulation and modulation of T helper cell responses. To test the effect of MV on macrophages in vitro, we have established a method to culture cotton rat macrophages. Cotton rat bone marrow-derived macrophages are phenotypically and functionally more similar to human than rodent macrophages because they secrete little nitric oxide. After infection with measles virus, macrophages produce less IL12 than uninfected macrophages. Based on studies in humans it has been hypothesized that the lack of IL12 might lead to a T helper type 2 (TH2) response which might be mechanistically linked to immune suppression. In cotton rats, IL12 secretion was suppressed after infection with both wildtype and vaccine virus. After stimulation of spleen or lymph node cells with MV antigen, only IFNγ was detected, indicative of a TH1 response. Cytokines compatible with a mixed TH0 response, IFN and IL4, were detectable in supernatants after stimulation with PMA/ionomycin. A recombinant vaccine virus which secretes cotton rat IL4 was used to investigate the contribution of a TH2 response to immune suppression. This virus enhanced IL4 secretion but did not increase T-cell proliferation inhibition. These data show that measles virus infection leads to a decrease in IL12 secretion and an increase in IL4 secretion but this does not seem to correlate with development of a TH2 response and immune suppression. Inhibition of T-cell proliferation following MV infection results from down regulation of AKT kinase activity. AKT is also a key signalling molecule in a number of pathways for primary macrophage functions. In cotton rats, wildtype and vaccine MV infection lead to a downregulation of AKT activity in macrophages concurrent with decreased phagocytosis and bacterial killing, and increased susceptibility to S. aureus pneumonia in vivo. Contrary to MV, many viruses activate the PI3K-AKT signaling pathway as a strategy to slow down apoptosis and increase virus replication. Our data indicate that an increased level of active AKT kinase does not significantly effect MV transcription, replication and progeny release. This leads us to conclude that MV growth is independent of AKT kinase activity and that MV-induced pAKT suppression may be purely a strategy to contain immune responses.
Stefan Niewiesk (Advisor)
Oglesbee Michael (Committee Member)
Schlesinger Larry (Committee Member)
Turner Joanne (Committee Member)
141 p.
Immunology; Virology
measles virus; immune suppression; cotton rat; macrophage; T helper 1; T helper 2; nitric oxide; interleukin 12; AKT

Recommended Citations

Citations

  • Carsillo, M. E. (2009). Mechanisms of Measles Virus-Induced Immune Suppression in the Cotton Rat Model [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1249584349

    APA Style (7th edition)

  • Carsillo, Mary. Mechanisms of Measles Virus-Induced Immune Suppression in the Cotton Rat Model. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1249584349.

    MLA Style (8th edition)

  • Carsillo, Mary. "Mechanisms of Measles Virus-Induced Immune Suppression in the Cotton Rat Model." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1249584349

    Chicago Manual of Style (17th edition)

osu1249584349
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© 2009, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.