Cytokine Modulation of the Innate Immune Response in Feline Immunodeficiency Virus–Infected Cats

Dean, Gregg A.; LaVoy, Alora; Yearley, Jennifer H.; Stanton, Christine

doi:10.1086/503873

Cited by 10 publications

(16 citation statements)

References 49 publications

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“…We have previously shown that chronically and acutely FIV-infected cats have an impaired innate immune response to the intracellular pathogen Lm [12],[13]. Here we showed that 3 days post-Lm challenge, chronically FIV-infected animals had a greater number of Lm colony-forming units per LN than SPF-control cats (64,280±31,253; 5,318±3,878 CFU/LN respectively, mean ± SEM).…”

Section: Resultssupporting

confidence: 50%

“…We previously reported that FIV-infected cats have an impaired innate response that fails to gain initial control of bacterial replication prior to the adaptive immune response [12]. We also demonstrated that locally delivered IL-15, a cytokine known to activate and stimulate NK cell proliferation, cytolytic activity, and cytokine and chemokine production, significantly restored innate immune function as measured by Lm clearance [13]. Here, we show that compared to SPF-control cats, NK cells from chronically FIV-infected cats have a constitutively higher level of proliferation that is counter-balanced by increased apoptosis.…”

Section: Introductionmentioning

confidence: 72%

“…We previously reported that FIV-infected cats had a delayed and blunted enlargement and follicle formation in draining LN after Lm challenge as compared to SPF-control cats [12], [13]. To further investigate this, LN were removed on day 3 after Lm challenge and the total number of cells was determined.…”

Section: Resultsmentioning

confidence: 99%

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In Vivo Assessment of Natural Killer Cell Responses during Chronic Feline Immunodeficiency Virus Infection

2012

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Accumulating evidence suggests that natural killer (NK) cells may have an important role in HIV-1 disease pathogenesis; however, in vivo studies are lacking. Feline immunodeficiency virus (FIV) infection of cats provides a valuable model to study NK cell function in vivo. The immune response against Listeria monocytogenes (Lm) is well characterized, allowing its use as an innate immune probe. We have previously shown that locally delivered IL-15 can improve Lm clearance in FIV-infected animals, and this correlated with an increase in NK cell number. In the present study, chronically FIV-infected and SPF-control cats were challenged with Lm by unilateral subcutaneous injection next to the footpad and then treated with 5-bromo-2′-deoxyuridine (BrdU). The Lm draining and contralateral control lymph nodes were evaluated for NK, NKT, CD4+ and CD8+ T cell number, proliferation, apoptosis, and NK cell function. Listeria monocytogenes burden was also assessed in both control and Lm draining lymph nodes. NK, NKT, CD4+ T and CD8+ T cells in the Lm-challenged lymph node of FIV-infected cats did not increase in number. In addition, after Lm challenge, NK cells from FIV-infected cats did not increase their proliferation rate, apoptosis was elevated, and perforin expression was not upregulated when compared to SPF-control cats. The failure of the NK cell response against Lm challenge in the draining lymph node of FIV-infected cats correlates with the delayed control and clearance of this opportunistic bacterial pathogen.

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Section: Resultssupporting

confidence: 50%

Section: Introductionmentioning

confidence: 72%

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In Vivo Assessment of Natural Killer Cell Responses during Chronic Feline Immunodeficiency Virus Infection

2012

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“…These data suggest that FIV-induced immunodeficiency may be derived from a failure to generate an IL-12 dependent response, in part due to elevated levels of IL10, which is known to suppress IL12 production by dendritic cells. In a more recent study, Dean et al (2006) reported a significant increase in bacterial numbers in FIV + cats compared to control cats as early as one day following L. monocytogenes infection, suggesting a poor innate immune response in the FIV + cats. In support of this, addition of IL15 increased NK activity and dramatically decreased the bacterial counts in co-infected cats (Dean et al, 2006).…”

Section: Cytokine Dysregulationmentioning

confidence: 95%

“…In a more recent study, Dean et al (2006) reported a significant increase in bacterial numbers in FIV + cats compared to control cats as early as one day following L. monocytogenes infection, suggesting a poor innate immune response in the FIV + cats. In support of this, addition of IL15 increased NK activity and dramatically decreased the bacterial counts in co-infected cats (Dean et al, 2006). In summary, although a clear TH1 to TH2 shift does not occur in FIV infection, the cytokine dysregulation leads to suppressed innate and CMI responses, resulting in the inability of an FIV + cat to mount a primary immune response to a secondary pathogen.…”

Section: Cytokine Dysregulationmentioning

confidence: 95%

Lentivirus-induced immune dysregulation

Tompkins

2008

Veterinary Immunology and Immunopathology

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FIV/HIV infections are associated with an early robust humoral and cellular anti-viral immune response followed by a progressive immune suppression that eventually results in AIDS. Several mechanisms responsible for this immune dysfunction have been proposed including cytokine dysregulation, immunologic anergy and apoptosis, and inappropriate activation of immune regulatory cells. Studies on FIV infection provide evidence for all three. Cytokine alterations include decreases in IL2 and IL12 production and increases in IFNγ and IL10 in FIV + cats compared to normal cats. The elevated IL10:IL12 ratio is associated with the inability of FIV + cats to mount a successful immune response to secondary pathogens. Additionally, chronic antigenic (FIV) stimulation results in an increase in the percent of activated T cells expressing B7 and CTLA4 costimulatory molecules in infected cats. The expression of these molecules is associated with T cells that are undergoing apoptosis in the lymph nodes. As ligation of CTLA4 by B7 transduces a signal for induction of anergy, one can speculate that the activated T cells are capable of T cell-T cell interactions resulting in anergy and apoptosis. The inability of CD4 + cells from FIV + cats to produce IL2 in response to recall antigens and the gradual loss of CD4 + cell numbers could be due to B7-CTLA4 interactions. The chronic antigenemia may also lead to activation of CD4 + CD25 + T regulatory cells. Treg cells from FIV + cats are chronically activated and inhibit the mitogen-induced proliferative response of CD4 + CD25 − by down-regulating IL2 production. Although Treg cell activation can be antigen specific, the suppressor function is not, and thus activated Treg cells would suppress responses to secondary pathogens as well as to FIV. Concomitant with the well known virus-induced immune suppression is a progressive immune hyper-activation. Evidence for immune hyper-activation includes polyclonal B cell responses, gradual replacement of naïve CD4 + and CD8 + T cell phenotypes with activation phenotypes (CD62L − , B7 + , CTLA4 + ), and the chronic activation of CD4 + CD25 + Treg cells. Thus lentivirus infections lead to severe immune dysregulation manifested as both chronic immune suppression and chronic immune activation. FIV infection of cats provides a number of advantages over other lentivirus infections as a model to study this immune dysregulation. It is a natural infection that has existed in balance with the cat's immune system for thousands of years. As such, the natural history and pathogenesis provides an excellent model to study the long term relationships between AIDS lentivirus and host immune system function/ dysregulation.

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Feline Immunodeficiency Virus Infection

Sykes¹

2014

Canine and Feline Infectious Diseases

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Cytokine Modulation of the Innate Immune Response in Feline Immunodeficiency Virus–Infected Cats

Abstract: Lentivirus infection impairs innate immune function in vivo, and IL-15 can significantly restore function. We hypothesize that altered dendritic-cell function and increased regulatory T cell activity may underlie the innate immune defect in HIV infection.

Cited by 10 publications

References 49 publications

In Vivo Assessment of Natural Killer Cell Responses during Chronic Feline Immunodeficiency Virus Infection

In Vivo Assessment of Natural Killer Cell Responses during Chronic Feline Immunodeficiency Virus Infection

Lentivirus-induced immune dysregulation

Feline Immunodeficiency Virus Infection

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