Primary viral infections (infections of non-immune individuals) are a major cause of morbidity and mortality in humans. Experimental and clinical data show that Natural Killer (NK) cells play an essential role in the control of many primary vira infections. The mechanisms of this control during the natural course of infection remain poorly defined. Many viruses relevant to human and animal health use a lympho- hematogenous (LH) route of spread whereby they breach epithelial surfaces and then spread stepwise through the regional draining lymph node (D-LN) and then the blood to produce a systemic disease. The Orthopoxvirus Ectromelia virus (ECTV), the agent of mousepox, is an outstanding model of natural infections and serves as the textbook example of viruses that disseminate through the LH route. We have previously shown that during the first two days after footpad ECTV infection of mousepox-resistant young C57BL/6 (B6) mice, activated mature NK cells accumulate in the D-LN. Importantly, we have also found that the mature NK cells that accumulate in the D-LN curb virus spread to the liver. This is critical for resistance to mousepox because mice succumb when their NK cells do not accumulate in the D-LN. Interestingly, B6 mice deficient in Toll Like Receptor 9 (TLR9) and its signaling adapter, MyD88 (MyD88) are highly susceptible to mousepox. Important for this application, mature NK cells do not accumulate in the D-LN of TLR9 and MyD88 deficient mice. The fundamental hypothesis in this application is that the accumulation of NK cells in the D-LN and their ability to curb virus spread is a major mechanism of defense against viruses that disseminate through the LH route. Thus, our major goals are to identify the molecular (Aim 1) and cellular (Aim 2) mechanisms that result in the specific accumulation of mature NK cells in the D-LN during ECTV infection with an emphasis on the role of the TLR9/MyD88 pathway and whether the virus subverts this process. Furthermore, we will determine whether comparable mechanisms of NK cell recruitment to the D-LN are operative during other viral infections and whether they contribute to decrease virus spread (Aim 3).
The proposed studies are highly significant because they will dissect a previously unknown mechanism of NK cell-mediated resistance to viral disease in a well studied model of lympho-hematogenous spread and extend the findings to other viruses. The proposed work is of significance to human health because the lympho-hematogenous route is a common mode of viral dissemination in humans. In the long term, our research may lead to novel approaches to induce viral resistance in humans by exploiting the ability of NK cells to curb virus spread.
|Remakus, Sanda; Ma, Xueying; Tang, Lingjuan et al. (2018) Cutting Edge: Protection by Antiviral Memory CD8 T Cells Requires Rapidly Produced Antigen in Large Amounts. J Immunol 200:3347-3352|
|Wong, Eric; Xu, Ren-Huan; Rubio, Daniel et al. (2018) Migratory Dendritic Cells, Group 1 Innate Lymphoid Cells, and Inflammatory Monocytes Collaborate to Recruit NK Cells to the Virus-Infected Lymph Node. Cell Rep 24:142-154|
|Fang, Min; Remakus, Sanda; Roscoe, Felicia et al. (2015) CD4+ T cell help is dispensable for protective CD8+ T cell memory against mousepox virus following vaccinia virus immunization. J Virol 89:776-83|
|Nair, Savita; Fang, Min; Sigal, Luis J (2015) The natural killer cell dysfunction of aged mice is due to the bone marrow stroma and is not restored by IL-15/IL-15R? treatment. Aging Cell 14:180-90|
|Xu, Ren-Huan; Wong, Eric B; Rubio, Daniel et al. (2015) Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection. Immunity 43:1148-59|
|Smith-Garvin, Jennifer E; Sigal, Luis J (2013) Immunology: Memory cells sound the alarm. Nature 497:194-6|
|Remakus, Sanda; Rubio, Daniel; Lev, Avital et al. (2013) Memory CD8? T cells can outsource IFN-? production but not cytolytic killing for antiviral protection. Cell Host Microbe 13:546-57|
|Rubio, Daniel; Xu, Ren-Huan; Remakus, Sanda et al. (2013) Crosstalk between the type 1 interferon and nuclear factor kappa B pathways confers resistance to a lethal virus infection. Cell Host Microbe 13:701-10|
|Remakus, Sanda; Sigal, Luis J (2013) Memory CD8? T cell protection. Adv Exp Med Biol 785:77-86|
|Fang, Min; Siciliano, Nicholas A; Hersperger, Adam R et al. (2012) Perforin-dependent CD4+ T-cell cytotoxicity contributes to control a murine poxvirus infection. Proc Natl Acad Sci U S A 109:9983-8|
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