Deficiencies in the innate immune response of HIV infected people and FIV infected cats are well documented. The defect often presents clinically as reduced competence in eliminating intracellular opportunistic pathogens. Not only is innate immunity responsible for the control and elimination of the majority of opportunistic infections, it is the innate response that initiates the type and strength of the adaptive immune response. We have employed Listeria monocytogenes (LM) as an immune system probe to investigate the effects of FIV infection on innate immune function. We have found that the innate immune response to LM is impaired in acutely and chronically FIV infected cats. We also determined that locally administered IL15 could improve the innate immune response and that this was associated with increased NK cells in draining lymph nodes. Activated, mature dendritic cells (DC) play a key role in initiating the innate immune response by recruiting and activating NK cells and modulating Treg function. It is now clear that cross-talk between DC, NK cells and Treg is critical for coordination of the innate response. As such, these three cell types create a fundamental regulatory axis for innate responses and subsequent adaptive responses. We will determine the contribution of each of these cell types to the innate immune defect associated with FIV infection.
Specific Aim 1 will determine whether incomplete DC maturation could underlie innate immune dysfunction during lentivirus infection and whether dendritic cells in FIV infected animals respond normally to TLR ligands.
Specific Aim 2 will determine the nature and mechanism of NK cell dysfunction in vivo. Specifically, this aim will assess NK cell chemotaxis, proliferation and function during an innate immune challenge of FIV+ cats, whether DC-NK cross-talk results in NK cell activation, and whether systemic IL15 treatment restores innate immune function.
Specific Aim 3 will determine if regulatory T cells suppress innate immune function in FIV infected cats, whether such an effect is mediated by TGF-? and if Treg are preferentially induced by DC. Together these studies will elucidate the cellular mechanisms that underlie the innate immune defect and investigate potential molecular mechanisms. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI047707-05A2
Application #
7339101
Study Section
Special Emphasis Panel (ZRG1-AARR-C (03))
Program Officer
Sharma, Opendra K
Project Start
2001-07-01
Project End
2011-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$334,125
Indirect Cost
Name
North Carolina State University Raleigh
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Zhang, Lin; Reckling, Stacie; Dean, Gregg A (2015) Phenotypic and functional analysis of CD1a+ dendritic cells from cats chronically infected with feline immunodeficiency virus. Comp Immunol Microbiol Infect Dis 42:53-9
Simoes, Rita D; Howard, Kristina E; Dean, Gregg A (2012) In vivo assessment of natural killer cell responses during chronic feline immunodeficiency virus infection. PLoS One 7:e37606
Wendelsdorf, K; Dean, G; Hu, Shuhua et al. (2011) Host immune responses that promote initial HIV spread. J Theor Biol 289:17-35
Mikkelsen, S Rochelle; Reckling, Stacie K; Egan, Erin A et al. (2010) In vivo depletion of CD4(+)CD25(hi) regulatory T cells is associated with improved antiviral responses in cats chronically infected with feline immunodeficiency virus. Virology 403:163-72
Lehman, Tracy L; O'Halloran, Kevin P; Fallon, Samantha A et al. (2009) Altered bone marrow dendritic cell cytokine production to toll-like receptor and CD40 ligation during chronic feline immunodeficiency virus infection. Immunology 126:405-12
Nordone, Sushila K; Ignacio, Glicerio A; Su, Lishan et al. (2007) Failure of TLR4-driven NF-kappa B activation to stimulate virus replication in models of HIV type 1 activation. AIDS Res Hum Retroviruses 23:1387-95
Dean, Gregg A; LaVoy, Alora; Yearley, Jennifer et al. (2006) Cytokine modulation of the innate immune response in feline immunodeficiency virus-infected cats. J Infect Dis 193:1520-7
Ignacio, Glicerio; Nordone, Shila; Howard, Kristina E et al. (2005) Toll-like receptor expression in feline lymphoid tissues. Vet Immunol Immunopathol 106:229-37
Sirriyah, Jamal; Dean, Gregg A; LaVoy, Alora et al. (2004) Assessment of CD4+ and CD8+ IFN-gamma producing cells by ELISPOT in naive and FIV-infected cats. Vet Immunol Immunopathol 102:77-84
Burkhard, Mary Jo; Dean, Gregg A (2003) Transmission and immunopathogenesis of FIV in cats as a model for HIV. Curr HIV Res 1:15-29