# Effect of obesity and diabetes in regulating pulmonary and extra-pulmonary anti-viral immune responses

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $769,522

## Abstract

ABSTRACT: Diabetes, particularly type 2 diabetes (T2D), is associated with hyperglycemia (Hg) and obesity
(Ob). Hg/Ob is associated with greater severity of disease and mortality in respiratory viral infections, such as
SARS-CoV-2 and Influenza. Hg/Ob exaggerates damaging inflammation and dampens anti-viral responses. To
address underlying mechanisms, we and others have established mouse models and report that in mice infected
with SARS-CoV-2, antecedent Hg/Ob: (1) reduces survival; and (2) increases inflammatory cytokines, TNF-
alpha, IL-alpha, IL-beta, and IL-9, all factors which recapitulate human disease. Our key preliminary data reveal
that in Hg/Ob, depletion of lung resident alveolar macrophages (AMs) significantly improves survival in SARS-
CoV-2 infection; in contrast, in lean mice, depletion of AMs causes significant mortality. These considerations
indicate that Hg/Ob significantly reprograms AMs to cause them to become highly proinflammatory, with
markedly reduced resolution potential. Strikingly, pre-infection, the lungs of mice and humans with Hg/Ob contain
an extensive network of adipose tissue and crown like structures, macrophages, including AMs. Hg/Ob augments
recruitment and invasion of immune cells, inflammation, and oxidative stress, thereby creating an environment
for deleterious responses to SARS-CoV-2. Hg/Ob mediates trained immunity; in mouse models, transplantation
of bone marrow from animals with T2D/Ob into control recipient mice amplifies atherosclerosis and
neuroinflammatory consequences, respectively, even after correction of Hg/Ob. In this Multi-PI application, Drs.
Kamal Khanna (expert in immunology, host responses to viruses and lung macrophages) and Ann Marie
Schmidt (expert in diabetes, obesity and metabolism), have worked together to develop the supporting data to
pursue the hypothesis that antecedent Hg/Ob reprograms pulmonary and extra-pulmonary immune responses,
thereby triggering loss of homeostatic immune cell-intrinsic and cell-cell crosstalk, and imbuing gain-of-toxic
function and deleterious loss-of-protective function in AM lung macrophages and in bone marrow myeloid
precursors; consequences of which include exacerbated and sustained tissue-damaging inflammation and
dampened resolution in respiratory viral infections. We predict that these consequences of Hb/Ob in
macrophages are mediated, at least in part, through striking upregulation of PLA2G7 in Hg/Ob AMs.
Our two laboratories, together with key collaborative support of Dr. VD Dixit (Yale), an expert in PLA2G7, will
employ state-of-the-art novel mouse models, bone marrow transplantation techniques, RNA/ATAC sequencing
and spatial transcriptomics, confocal microscopy, flow cytometry including novel methodologies to track
immune cell metabolism and other methods in mice infected with mouse-adapted SARS-CoV-2, MA-10 or PR8
(influenza). The significance and impact of this work is very high. As the epidemics of T2D and obesity
continue to soar, it is es...

## Key facts

- **NIH application ID:** 10999623
- **Project number:** 1R01DK138675-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Kamal Mohan Khanna
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $769,522
- **Award type:** 1
- **Project period:** 2024-07-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999623

## Citation

> US National Institutes of Health, RePORTER application 10999623, Effect of obesity and diabetes in regulating pulmonary and extra-pulmonary anti-viral immune responses (1R01DK138675-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10999623. Licensed CC0.

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