# Mechanisms of age-related susceptibility to the chikungunya virus (CHIKV)

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $337,700

## Abstract

Abstract
Chikungunya virus (CHIKV) is a reemerging alphavirus that recently spread throughout the world via its
mosquito vectors. The virus has high potential to inflict significant morbidity and mortality worldwide, including
the U.S., with initial transmissions reported in Florida. Older adults are particularly sensitive to severe CHIKV
disease (CHIKVD), which includes fever, rash, joint pain and sometimes involvement of parenchymal organs
(liver, brain, kidney). Moreover, CHIKVD tends to persist in many, particularly older, subjects in the form of
highly debilitating arthritis/arthralgia for months and years. While we are beginning to understand CHIKV
pathogenesis and immunity, we are far from even scratching the surface on the mechanisms of age-related
vulnerability to CHIKV.
We recently developed a mouse model which recapitulates age-related clinical outcomes observed in CHIKV-
infected elderly humans, and used it to begin to elucidate mechanisms underlying the age-related dysfunction
of the immune response to CHIKV infection. We found an increase in TGFβ, concomitant with qualitative and
quantitative impairments in B and T cell responses which failed to clear the virus. We showed that anti-TGFβ
antibody blockade could prevent the age-related increase in CHIKV disease severity, reduce joint pathology
and improve production of neutralizing antibodies. TGFβ was also elevated and neutralizing Ab reduced in
older humans suffering from CHIKV, making our model potentially directly relevant to older adults. Here, we
propose to dissect mechanisms that lead to dysregulated TGFβ production and to elucidate how TGFβ
contributes to increased pathology and decreased CHIKV control. Our central hypothesis is that that in old
CHIKV-infected mice, increased TGFβ dysregulates type 1 (T1) immunity against CHIKV by acting
upon soluble factors, Th1, B and perhaps Th17, cells. This hypothesis and related questions and sub-
hypotheses will be tested in the following Aims:
 SA1. To test the roles of T and B cell-intrinsic and extrinsic (environmental) factors in suboptimal
adaptive responses of old mice to CHIKV.
 SA2. To examine whether and how elevated TGFβ acts directly on old adaptive immune cells.
 These experiments will provide detailed insights into pathogenesis and immunity against CHIKV and pave
the way for immune interventions against CHIKVD/chronic arthritis in older adults.

## Key facts

- **NIH application ID:** 9953941
- **Project number:** 5R01AG057701-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** JANKO Z. NIKOLICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,700
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953941

## Citation

> US National Institutes of Health, RePORTER application 9953941, Mechanisms of age-related susceptibility to the chikungunya virus (CHIKV) (5R01AG057701-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9953941. Licensed CC0.

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