Elucidating influenza-induced protection of malaria-associated respiratory distress syndrome in mice

Active Project Grant Awarded Last action

Award ID
R21AI185994
Recipient
Awarding agency
Obligated
$416,570

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 79% complete
Place of performance
Salt Lake City, UT 84112, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The focus of the research in the lamb lab is to determine mechanisms of the immunopathogenesis of malaria. The long-term goal of the proposed work is to determine the molecular mechanisms of vascular leak in malaria. IT is estimated that annually more than ~250 million people develop malaria worldwide resulting in over 600,000 deaths[1]. Malaria-associated respiratory distress syndrome (MA-ards) and malaria-associated acute lung injury (MA-ALI) are features of adult malaria where infection is caused by the species plasmodium knowlesi and plasmodium vivax. Despite the poor prognosis of this syndrome in malaria, very little is understood about the molecular players that mediate pulmonary vascular leak in MA-ards / MA-ALI. As such IT is difficult to design new adjunct therapeutic strategies for this condition. CD8 t cell responses against the plasmodium parasites that cause malaria are responsible for the pathogenesis of infection and are required for pulmonary vascular leak. Here we investigate our fascinating finding that CO-infection of influenza with p. Berghei NK65E prevents MA-ards / MA-ALI in mice. The proposed work will capitalize on this finding to establish the mechanisms by which protection occurs. Our published and preliminary data leads US to test the working hypothesis of this study that influenza modifies pulmonary vascular endothelial cells (pmvecs) and induces arginase 1 (ARG1)-producing monocytes as key protective mechanisms against CD8-mediated MA- ards / MA-ALI. Staggering of influenza a/X31 CO-infection reveals protection only occurs when X31 infects at the same time as p. Berghei NK65E suggesting an innate immune mechanism at play. We show that influenza a/X31 recruits a large number of ARG1-producing monocytes which are capable of suppressing the proliferation of polyclonally stimulated CD8 t cells. The rationale for the proposed work is that CD8 t cell responses are central to pulmonary vascular leak associated with malaria, and a more comprehensive understanding of how influenza prevents this damaging response will provide key information for the rational design of novel interventions to reverse pulmonary vascular leak in MA-ards / MA-ALI. We plan to test our central hypothesis and thereby accomplish the objective of this application by pursuing the following two specific aims: aim 1: determine whether influenza CO-infection can suppress the pathogenic response of plasmodium-reactive CD8 t cells directly or indirectly. Aim 2: test the hypothesis that influenza-induced ARG1+ monocytes protect NK65E-infected mice from vascular leak.

Transactions

Action Obligated Date
Amendment $192,500
Original award $224,070

Quick answers

Who received award R21AI185994?

R21AI185994 was awarded to University Of Utah by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on February 24, 2025.

How much is award R21AI185994 worth?

$416,570 has been obligated on R21AI185994.

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