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 3

RSV infection is efficiently controlled by the human immune system in BLT-L mice and elicits protective immunity from a second RSV challenge.

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RSV infection is efficiently controlled by the human immune system in BL...
(A) Bioluminescence (radiance [p sec–1 cm–2 sr–1] represented as total flux) in human lung implants of RSV A2-Luc exposed LoM (blue bars, n = 6 implants) and BLT-L mice (red bars, n = 8 implants). Dashed line indicates background (preexposure) luminescence. (B) RSV antigen (brown) in LoM (n = 4 implants analyzed/time point) and BLT-L mouse (n = 4 implants analyzed/time point) lung implants on days 4, 11, and 21 after exposure. Scale bars: 100 μm. (C) BLT-L mouse lung implants were inoculated with RSV A2-GFP or vehicle (first exposure) and then RSV A2-Luc 21 days later (second exposure). (D) Bioluminescence signal in lung implants of RSV A2-Luc–exposed BLT-L mice that were exposed first to RSV A2-GFP (n = 6 implants; yellow bars) or vehicle (n = 12 implants; gray bars). The median (horizontal line), upper and lower quartiles (box ends), and minimum to maximum values (whiskers) are shown. Dashed line indicates background luminescence (day 0). (E and F) RSV-specific human (E) IgM and (F) IgG plasma levels in naive BLT-L mice (n = 4) and BLT-L mice exposed once (IgM, n = 9; IgG, n = 10) or twice (IgM, n = 11; IgG, n = 9) to RSV. Dashed line indicates seropositivity threshold. (G) RSV neutralization activity of plasma from naive BLT mice (n = 4) and BLT mice exposed once (n = 5) or twice (n = 8) to RSV. Shown is the number of RSV GFP+ cells 72 hours after infection representative of 6 replicates. (H) RSV NP137-145 pentamer-reactive CD8+ T cells in the lung implant of a BLT-L mouse exposed twice to RSV. (E–G) Data are shown as mean ± SEM. Two-tailed (A and D) Mann-Whitney U, and (G) Kruskal-Wallis tests were used to determine statistical significance. P values were adjusted for multiple testing using the Benjamini, Krieger, and Yekutieli FDR method.