Specific Aim1: Investigation of in situ NK cell and neutrophil responses during MmuPV1 infection and tumor development
Rationale: Innate immune cells including NK cells, monocytes, neutrophils, macrophages, and DCs play a crucial role during the early phase of the viral infection (36, 40, 62). We hypothesize that differential disease outcomes are associated with local immune cell populations and their activity. Neutrophils are the first and most abundant cell population that reaches sites of viral infection and exhibit both protective and pathologic functions (36, 63). In vitro study showed that HPV16 E6 and E7 cooperatively disrupted IL-8 transcription, a chemotactic factor for attracting neutrophils to the infected sites (35). Depletion of …show more content…
Comparing the absolute population of NK cells and neutrophils among them may be difficult without taking their various baselines into consideration. We have included a non-infected group of each mouse strain for proper comparisons. Although we expect to detect the diverse composition of NK cells and neutrophils at different anatomic locations on the same animal, some studies showed that the activation rather the absolute numbers of the immune cells are crucial (40). Neutrophil depletion was found to impair NK cell maturation, function, and homeostasis in a recent study (70) Therefore, the outcome of neutrophil depletion may be contributed partly by NK cell dysfunction. To distinguish the activation of NK cells and neutrophils, we have included a panel of antibodies. To attest the role of activated NK cells in the local host defense, we can apply IL-12 to the local infection sites to explore whether the disease burden will be reduced. Studies showed different HPV types may evade innate immune responses differently (6). But no studies have focused on tissue-specific mechanisms by which HPV evade immune response. Studies using this broad tissue tropism model will shed light on the tissue tropism of the HPV infection. Several gene modified mice that target NK cells and neutrophils (IL-15−/− and CXCR2−/−) are available (36, 37, 69). However, these mice are generated on other genetic backgrounds and therefore might not be adequate to delineate the role of these cells of our test mice. We can generate IL-15−/− and CXCR2−/−mice in our mouse strains if needed. Human studies in the host control of viral infection have faced the challenge of lack of consistency due to the convoluted nature of the experimental design (70). Our
Rationale: Innate immune cells including NK cells, monocytes, neutrophils, macrophages, and DCs play a crucial role during the early phase of the viral infection (36, 40, 62). We hypothesize that differential disease outcomes are associated with local immune cell populations and their activity. Neutrophils are the first and most abundant cell population that reaches sites of viral infection and exhibit both protective and pathologic functions (36, 63). In vitro study showed that HPV16 E6 and E7 cooperatively disrupted IL-8 transcription, a chemotactic factor for attracting neutrophils to the infected sites (35). Depletion of …show more content…
Comparing the absolute population of NK cells and neutrophils among them may be difficult without taking their various baselines into consideration. We have included a non-infected group of each mouse strain for proper comparisons. Although we expect to detect the diverse composition of NK cells and neutrophils at different anatomic locations on the same animal, some studies showed that the activation rather the absolute numbers of the immune cells are crucial (40). Neutrophil depletion was found to impair NK cell maturation, function, and homeostasis in a recent study (70) Therefore, the outcome of neutrophil depletion may be contributed partly by NK cell dysfunction. To distinguish the activation of NK cells and neutrophils, we have included a panel of antibodies. To attest the role of activated NK cells in the local host defense, we can apply IL-12 to the local infection sites to explore whether the disease burden will be reduced. Studies showed different HPV types may evade innate immune responses differently (6). But no studies have focused on tissue-specific mechanisms by which HPV evade immune response. Studies using this broad tissue tropism model will shed light on the tissue tropism of the HPV infection. Several gene modified mice that target NK cells and neutrophils (IL-15−/− and CXCR2−/−) are available (36, 37, 69). However, these mice are generated on other genetic backgrounds and therefore might not be adequate to delineate the role of these cells of our test mice. We can generate IL-15−/− and CXCR2−/−mice in our mouse strains if needed. Human studies in the host control of viral infection have faced the challenge of lack of consistency due to the convoluted nature of the experimental design (70). Our