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Role of cell-to-cell transmission in alphavirus infection and disease

Award Number: R21AI188908
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: 11/20/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Role of cell-to-cell transmission in alphavirus infection and disease - PROJECT SUMMARY Alphaviruses include important and emerging human pathogens such as the arthritogenic alphaviruses chikungunya virus (CHIKV) and Mayaro virus (MAYV). These viruses are disseminated by mosquito vectors and cause acute febrile illness with severe joint pain that can progress to chronic polyarthritis. It is unclear if chronic disease results from persistent virus infection of joint tissues and/or from host inflammatory responses. CHIKV has emerged over the last 15 years to cause millions of human infections world-wide, resulting in severe long-term health and economic consequences. Our recent collaborative work demonstrated that CHIKV infection induces the formation of intercellular long extensions (ILE) that reach from the infected cell to neighboring cells. These stable non-continuous connections mediate CHIKV cell-to-cell (CC) transmission, a mode of infection that is resistant to high concentrations of neutralizing antibodies (Abs) both in vitro and in vivo. We also showed that ILE formation and CC transmission can be blocked by distinct monoclonal Abs (mAbs) to the viral envelope proteins. This proposal is a collaborative effort by the Kielian and Morrison groups to define the viral envelope targets for Ab-mediated inhibition of CC spread, the cell types infected by CC spread, and the importance of this pathway in alphavirus infection and disease. The specific aims are: 1. Determine mechanisms by which Abs block alphavirus CC spread. We will use a panel of mAbs to define the envelope protein domains that are targeted to inhibit CC spread. Serum samples from CHIKV patients will be tested for inhibition of CC spread, and results correlated with known disease progression and envelope protein targets. We will also determine if MAYV infection induces ILE and CC spread, and if CHIKV and MAYV can use this pathway in mosquito cells. 2. Elucidate the contribution of CC spread to CHIKV cellular tropism, dissemination and disease, and viral persistence in vivo. Using our mouse models of infection, we will employ defined mAbs that do or do not inhibit CC spread to determine the stromal and hematopoietic cells that are infected by this pathway. Using Rag1-/- mice that lack endogenous Ab we will determine if Ab-mediated inhibition of CC spread is required to limit viral dissemination and/or persistent CHIKV infection. We will use highly susceptible Ifnar1-/- mice to determine if mAb inhibition of CC spread can block disease development. The results of our studies will provide fundamental information on alphavirus CC transmission, and can help to develop more effective Ab-based therapies and vaccines against alphavirus-induced 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: 2026 ( Subtotal = $202,098 )
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	2	11/27/2025	NON-COMPETING CONTINUATION	$202,098
														Subtotal = $202,098

Issue Date FY: 2025 ( Subtotal = $253,265 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	1	2/12/2025	NEW	$0
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	11/20/2024	NEW	$253,265
														Subtotal = $253,265

Grand Total All Awards = $455,363

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Role of cell-to-cell transmission in alphavirus infection and disease

Award Number: R21AI188908

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: 11/20/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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