Human T cells efficiently control RSV infection
Chandrav De, Raymond J. Pickles, Wenbo Yao, Baolin Liao, Allison Boone, Mingyu Choi, Diana M. Battaglia, Frederic B. Askin, Jason K. Whitmire, Guido Silvestri, J. Victor Garcia, Angela Wahl
Chandrav De, Raymond J. Pickles, Wenbo Yao, Baolin Liao, Allison Boone, Mingyu Choi, Diana M. Battaglia, Frederic B. Askin, Jason K. Whitmire, Guido Silvestri, J. Victor Garcia, Angela Wahl
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Research Article Immunology Virology

Human T cells efficiently control RSV infection

Abstract

Respiratory syncytial virus (RSV) infection causes significant morbidity and mortality in infants, immunocompromised individuals, and older individuals. There is an urgent need for effective antivirals and vaccines for high-risk individuals. We used 2 complementary in vivo models to analyze RSV-associated human lung pathology and human immune correlates of protection. RSV infection resulted in widespread human lung epithelial damage, a proinflammatory innate immune response, and elicited a natural adaptive human immune response that conferred protective immunity. We demonstrated a key role for human T cells in controlling RSV infection. Specifically, primed human CD8+ T cells or CD4+ T cells effectively and independently control RSV replication in human lung tissue in the absence of an RSV-specific antibody response. These preclinical data support the development of RSV vaccines, which also elicit effective T cell responses to improve RSV vaccine efficacy.

Authors

Chandrav De, Raymond J. Pickles, Wenbo Yao, Baolin Liao, Allison Boone, Mingyu Choi, Diana M. Battaglia, Frederic B. Askin, Jason K. Whitmire, Guido Silvestri, J. Victor Garcia, Angela Wahl

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Figure 1

Sustained replication of RSV in human lung implants.

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Sustained replication of RSV in human lung implants. (A and B) H&E s...
(A and B) H&E staining of (A) a naive LoM human lung implant (n = 5 implants analyzed) and (B) a human lung implant from an RSV-infected LoM (n = 12 implants analyzed). Scale bars: 200 μm. Arrows note airways. (C) RSV-RNA expression in the human lung implants of control (2 hours after RSV exposure) and RSV-infected LoM at 4 and 11 days after exposure (n = 5 implants/time point). Crossing point (Cp) indicates the cycle number at which the fluorescence signal of the sample exceeds a background fluorescence value. (D) RSV titers (log10TCID50/mL) in human lung implants of control LoM (2 hours after RSV exposure) and RSV-infected LoM at 4 days and 11 days after RSV exposure (n = 5 implants/time point). Dashed line indicates the assay limit of detection. (E) Number of GFP+ cells as determined by flow cytometry in the human lung implants of naive LoM (n = 4 implants) and RSV A2-GFP–infected LoM 4, 7, 11, 14, and 21 days after exposure (n = 4 implants/time point). (F) RSV replication monitored longitudinally in the human lung implants of RSV-Luc infected LoM (n = 6 implants) as measured by bioluminescence (radiance [p sec–1 cm–2 sr–1] represented as total flux) signal. The median (horizontal line), upper and lower quartiles (box ends), and minimum to maximum values (whiskers) are shown. Background luminescence (day 0) is denoted by the dashed line. (G) IHC staining for RSV antigen in the human lung implants of naive LoM (n = 4 implants analyzed) and RSV-infected LoM 4, 7, and 21 days after exposure (positive cells are brown, n = 4 implants analyzed/time point). Scale bars: 200 μm. (C–E) Data are shown as the mean ± SEM; (C and D) a statistical analysis was performed using a 2-tailed Kruskal-Wallis test. P values were adjusted for multiple testing using the Benjamini, Krieger, and Yekutieli FDR method.