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Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection

Award Number: R01AI145997
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection - Project Summary Natural killer (NK) cells are lymphocytes of the immune system that can detect and kill virally infected cells. Epidemiological studies have shown that immunosuppressed (e.g. cancer, organ transplant, AIDS) patients and newborns display an enhanced risk for health complications associated with human cytomegalovirus (HCMV) infection that can be life-threating. Previous work has shown that mouse cytomegalovirus (MCMV) infection in mice can accurately model HCMV infection, and demonstrated that NK cells are critical for the control of MCMV. Furthermore, NK cells have been shown to have properties of the adaptive immune system such as recall responses, antigen-specificity, and clonal expansion in mice, macaques, and humans. Although our work has made significant progress into elucidating how autophagy and mitophagy lead to the generation of memory NK cells and the survival of proliferating lymphocytes, the upstream regulatory elements of these fundamental biological processes remain poorly understood in lymphocytes in vivo. Our long-term goals seek to identify the relevant transcriptional signals that induce autophagy, mitophagy, and survival of memory NK cells following viral infection. In RNA-sequencing experiments, we have identified Trp73 (p73) as a transcription factor selectively enriched in memory NK cells following murine cytomegalovirus (MCMV) infection. Further experimental validation by qRT-PCR revealed that two dominant isoforms of Trp73 in mice (TAp73 and ΔNp73) display distinct temporal expression patterns in NK cells during MCMV infection. Importantly, the roles of p73 transcriptional isoforms in lymphocyte responses to viral infection in vivo are unknown. Our exciting preliminary findings suggest that ΔNp73 is transiently induced in effector NK cells and is required for clonal expansion and generation of memory NK cells. In contrast, TAp73 expression is sustained in effector and memory NK cells and is dispensable for effector NK proliferation, but critical for the survival and generation of memory NK cells. In Aim 1, we will determine whether TAp73 influences autophagic removal of dysfunctional mitochondria in NK cells to promote the survival of effector NK cells as they transition to memory cells using cutting-edge autophagy and metabolism assays. In Aim 2, we will determine whether ΔNp73 leads to the proliferation of effector NK cells through repression of p53 to shield NK cells from apoptosis or relieve cell cycle repression. In Aim 3, we will perform RNA and ChIP-sequencing experiments to determine the gene targets of p73 in effector NK cells using genomic analyses. In summary, the proposed studies included in this R01 proposal will contribute to our basic understanding of how primary cells induce mitophagy in vivo, while also contributing to novel clinical strategies to enhance the use of adaptive NK cell responses for immunization against 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 = $453,462 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	4/7/2023	NON-COMPETING CONTINUATION	$453,462
														Subtotal = $453,462

Issue Date FY: 2022 ( Subtotal = $453,462 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	3/25/2022	NON-COMPETING CONTINUATION	$453,462
														Subtotal = $453,462

Issue Date FY: 2021 ( Subtotal = $453,462 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	4/2/2021	NON-COMPETING CONTINUATION	$453,462
														Subtotal = $453,462

Issue Date FY: 2020 ( Subtotal = $453,462 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	3/20/2020	NON-COMPETING CONTINUATION	$453,462
														Subtotal = $453,462

Issue Date FY: 2019 ( Subtotal = $453,462 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	5/6/2019	NEW	$453,462
														Subtotal = $453,462

Grand Total All Awards = $2,267,310

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Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection

Award Number: R01AI145997

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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