# Spread and Release of Measles in the Airways

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $689,072

## Abstract

PROJECT SUMMARY:
Humans are the only natural reservoir for the extremely contagious measles virus (MeV). Thus, a critical
challenge for MeV study is identification of representative human model systems. For decades, MeV was
thought to enter the human host through the apical surface of airway cells, a misconception based on studies
in immortalized cell lines. Well-differentiated primary cultures of airways epithelial cells from human donors
(HAE) provide a more physiological relevant model of human airways. Using HAE, we found that MeV
exclusively enters the basolateral membrane. This observation lead to a completely new paradigm for how
MeV enters the human host. In addition to basolateral entry, we observed that MeV infection of HAE results in
the formation of infectious centers that retain intact plasma membranes and are substantially different than
the syncytia observed in immortalized cells. Infectious centers differ from syncytia in two important ways: 1)
infectious centers stop growing 3-4 days post-infection and 2) infectious centers disappear after ~10 days
leaving the cell layer intact. Why infectious centers stop growing and how they disappear in HAE remain a
mystery and is the focus of this application. We hypothesize that infectious center formation in the respiratory
epithelium is a vital step in the final amplification process before release to the next host. In Aim 1, we define
the innate immune response pathways in the airways. We quantify 14 antiviral sentinel genes at 12 timepoints
ranging from 6 hours to 2 weeks. In addition, laser capture of infectious centers is used to isolate infected cells
from uninfected cells within an epithelial sheet and deep sequencing is used to map the cellular response to
MeV. In Aim 2, we address how MeV is released from HAE. Preliminary data suggest that infectious centers
are shed, intact, from the HAE (rather than rupturing). The timecourse and frequency of shedding will be
defined. The roles of cell proliferation and cell death pathways will be probed by cell labeling to discern how
large infectious centers can be released yet the epithelial integrity is maintained. MeV mediated cytoskeletal
modifications are likely to be mechanistically involved in infectious center release, which we test using
inhibitors of F-actin treadmilling. In Aim 3, we hypothesize that shed infectious centers are physiologically
relevant vectors for MeV delivery. We will deliver cell-associated and cell-free MeV to the airways of rhesus
macaques and quantify the time-course of infection. This aim has the potential to reshape a fundamental
dogma of how MeV is spread host-to-host. In summary, these studies use an appropriate model system to
study MeV entry, spread, and luminal release. Our research will elucidate mechanisms by which the most
contagious human respiratory virus undergoes its final amplification step before release to its next host.

## Key facts

- **NIH application ID:** 9953927
- **Project number:** 5R01AI132402-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** PATRICK L SINN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $689,072
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953927

## Citation

> US National Institutes of Health, RePORTER application 9953927, Spread and Release of Measles in the Airways (5R01AI132402-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9953927. Licensed CC0.

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