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Distinct innate immune responses to HSV-1 versus HSV-2 genital infection determine extent of neuronal infection.

Award Number: F30AI161309
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY/ABSTRACT Genital herpes (GH) is a common sexually transmitted infection with significant morbidity and no vaccine or cure. It is caused by Herpes Simplex Virus-1 (HSV-1) or HSV-2. Patients who have HSV-2 GH experience significantly higher frequency of disease recurrence and transmission than patients with HSV-1 GH. Previous studies linked frequency of reactivation to reservoirs of latent virus in the peripheral nervous system (PNS) that were consistently larger after HSV-2 genital infection relative to HSV-1. However, it was unknown whether these disparate outcomes were due to intrinsic viral properties or the host response. To explore the latter, our lab utilizes direct comparisons of murine models of HSV-1 and HSV-2 vaginal infection. From these, we identified that HSV-1 induces an accelerated adaptive immune response relative to HSV-2, better protecting the PNS from viral invasion. Increased neuroprotection was linked to an early burst of NK cell dependent IFNg that was secreted in the vagina one day after HSV-1 but not HSV-2 infection. However, the upstream signals driving differential kinetics of NK activation between each model as well as the downstream mechanisms conferring increased neuronal resistance to infection are both unknown. The central hypothesis of this proposal is that HSV- 1 genital infection is sensed by local immune cells faster than HSV-2, leading to rapid mucosal secretion of IFN¿ that directly enhances neuronal resistance to infection. Previous studies have identified a key role for inflammatory monocyte IL-18 in activating NK cells to produce IFNg during HSV-2 infection. Preliminary data suggests a trend towards faster recruitment of this population during HSV-1 infection, correlating with earlier IFNg production. To follow up, I will compare the mechanism of inflammatory monocyte recruitment during HSV- 1 vs HSV-2 infection and identify the distinct responses that differentially regulate vaginal NK cell recruitment IFNg production (Aim 1). IFNg is a known inducer of autophagy in other host-pathogen responses, and autophagy is one of the primary non-lytic mechanisms by which sensory neurons control HSV infection. Therefore, I will also explore the novel potential crosstalk between mucosal NK cells and the PNS by evaluating whether IFNg can augment autophagic flux in sensory neurons in vitro and in vivo as a mechanism to control HSV infection (Aim 2). The long-term objective of this proposal is to define the distinct innate immune responses to HSV-1 vs HSV-2 genital infection as a method to identify the requisite features of a host response that successfully limits neuronal invasion. Such investigation would be invaluable for informing future vaccine design that is effective against both viruses. In pursuit of this first objective, I will achieve my second objective of further developing my autonomy as an independent researcher through a carefully crafted training plan developed with my sponsor, Dr. Haina Shin, and co-sponsor, Dr. Wayne Yokoyama, that will i) enhance my research skills, ii) strengthen my abilities in scientific communication, and iii) provide mentorship and professional development opportunities to achieve my career goals to be a future physician-scientist and academic investigator in infectious disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $52,174 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	2	2/15/2023	NON-COMPETING CONTINUATION	$942
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	2	11/10/2022	NON-COMPETING CONTINUATION	$51,232
														Subtotal = $52,174

Issue Date FY: 2022 ( Subtotal = $32,686 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	002	1	5/4/2022	NEW	$717
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	11/19/2021	NEW	$31,970
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	003	1	5/25/2022	NEW	-$1
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	1	11/19/2021	NEW	$0
														Subtotal = $32,686

Grand Total All Awards = $84,860

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Distinct innate immune responses to HSV-1 versus HSV-2 genital infection determine extent of neuronal infection.

Award Number: F30AI161309

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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