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Coordination of innate and cellular mucosal immunity in SARS-CoV-2 clearance

Award Number: R01AI188896
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Coordination of innate and cellular mucosal immunity in SARS-CoV-2 clearance - SUMMARY Neutralizing antibodies against SARS-CoV-2 are a strong correlate of protection against severe disease, hospitalization, and death. However, a combination of waning immunity and evolution of immune-evasive variants jeopardizes vaccine-mediated immunity. While there has been a strong research emphasis on humoral immunity, we still have a limited understanding of how mucosal innate and T cell responses contribute to SARS- CoV-2 viral control and clearance. The first few days of SARS-CoV-2 infection are marked by a transient antiviral type I interferon (IFN) response and proinflammatory cytokine and chemokine induction concomitant with mobilization of inflammatory CCR2-monocytes that traffic into the respiratory tract. Using C57BL/6 mice with a naturally occurring pathogenic SARS-CoV-2 variant (B.1.351), we previously determined the importance of CCR2- monocytes in mediating protective immunity against SARS-CoV-2. These innate immune responses are followed by the development of virus-specific antibodies and T cell responses that mediate viral control and lead to clearance. While these studies and many others have shown how aberrant immune responses at any of these stages can lead to a defect in viral control and deleterious immunopathology, most have focused exclusively on the lower respiratory tract , i.e. the lungs. In contrast, few studies have investigated the orchestration of immunity in the upper respiratory tract (URT), the site of initial virus transmission and replication, and how the individual components of the immune response contribute to viral control at this site. Here, we present evidence showing that the contributions of monocytes and T cells in promoting viral control differ between the upper and lower respiratory tract (LRT), as these responses were critical for clearance in the URT but not the LRT. We demonstrate that MYD88 signaling and inflammatory monocytes are critical for controlling early viral replication in the nasal cavity. We also found that while antigen-specific T cells infiltrate the both the nasal compartment and lungs early during infection, T cells appear to contribute a minimal role in promoting viral control and clearance in the lungs. In contrast, both CD4+ and CD8+ T cells in the nasal compartment are required for preventing persistent and culturable virus replication within nasal epithelial cells. Based on our findings, we hypothesize that the coordinated responses of inflammatory monocytes and virus-specific T cells in the upper respiratory tract are necessary to limit early viral replication and prevent viral persistence at this site. In Aim 1 we will determine the contribution of monocytes in promoting T cell responses and viral control within the respiratory tract. In Aim 2, we will define the effector mechanisms of protective mucosal T cell responses against SARS-CoV-2 infection and persistence in the URT versus LRT. Both Aims will explore these questions in the context of primary and vaccine breakthrough infections using our novel murine model of suboptimal versus protective vaccination. Overall, these studies will advance our understanding of protective mucosal innate and T cell responses that can leveraged for next-generation vaccines against SARS-CoV-2.


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: 2026 ( Subtotal = $721,118 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	2	12/3/2025	NON-COMPETING CONTINUATION	$721,118
														Subtotal = $721,118

Issue Date FY: 2025 ( Subtotal = $705,557 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	1	12/19/2024	NEW	$705,557
														Subtotal = $705,557

Grand Total All Awards = $1,426,675

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Coordination of innate and cellular mucosal immunity in SARS-CoV-2 clearance

Award Number: R01AI188896

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/20/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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