Nasal priming by a murine coronavirus provides protective immunity against lethal heterologous virus pneumonia
Xiaoyang Hua, … , Stephen Tilley, Stanley Perlman
Xiaoyang Hua, … , Stephen Tilley, Stanley Perlman
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e99025. https://doi.org/10.1172/jci.insight.99025.
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Research Article Immunology Virology

Nasal priming by a murine coronavirus provides protective immunity against lethal heterologous virus pneumonia

Abstract

The nasal mucosa is an important component of mucosal immunity. Immunogenic particles in inspired air are known to activate the local nasal mucosal immune system and can lead to sinonasal inflammation; however, little is known about the effect of this activation on the lung immune environment. Here, we showed that nasal inoculation of murine coronavirus (CoV) in the absence of direct lung infection primes the lung immune environment by recruiting activated monocytes (Ly6C+ inflammatory monocytes) and NK cells into the lungs. Unlike infiltration of these cells into directly infected lungs, a process that requires type I IFN signaling, nasally induced infiltration of Ly6C+ inflammatory monocytes into the lungs is IFN-I independent. These activated macrophages ingested antigen and migrated to pulmonary lymph nodes, and enhanced both innate and adaptive immunity after heterologous virus infection. Clinically, such nasal-only inoculation of MHV-1 failed to cause pneumonia but significantly reduced mortality and morbidity of lethal pneumonia caused by severe acute respiratory syndrome CoV (SARS-CoV) or influenza A virus. Together, the data indicate that the nose and upper airway remotely prime the lung immunity to protect the lungs from direct viral infections.

Authors

Xiaoyang Hua, Rahul Vijay, Rudragouda Channappanavar, Jeremiah Athmer, David K. Meyerholz, Nitin Pagedar, Stephen Tilley, Stanley Perlman

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Figure 1

Nasal administration of MHV-1 dramatically reduced mortality and morbidity of lethal pneumonia by heterologous viruses.

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Nasal administration of MHV-1 dramatically reduced mortality and morbidi...
BALB/c mice were intranasally infected with MHV-1 (2 μl, 104 PFU) or vehicle. Two days later, mice were infected with SARS-CoV (104 PFU) or IAV (PR-8 strain, 1,160 TCIU) (50 μl per mouse via IT instillation). The negative controls were mice that only received vehicle. Mortality and morbidity were then monitored daily. Mice that lost >30% of their initial weight were euthanized per institutional IACUC protocols. (A) Survival rates of SARS-CoV–infected mice. P < 0.0001, SARS (n = 10) vs. MHV+SARS (n = 10) and MHV+vehicle (MHV+Veh) (n = 5). No difference was found between MHV+SARS and MHV+Veh, using both log-rank (Mantel-Cox) test and Gehan-Breslow-Wilcoxon test. (B) Weight is expressed as percentage of original weight. **P < 0.01, among MHV-SARS (n = 10), SARS (n = 10), and MHV+Veh (n = 5) using repeated-measures ANOVA; P < 0.01, MHV-SARS vs. SARS, using LSD. (C) Viral titers at 6 days p.i. **P < 0.001, MHV-SARS (n = 5) vs. SARS (n = 5). (D–G) Lung histology: D (×10) and E (×40), representative from MHV-SARS group; F (×10) and G (×40), representative from SARS group. Hemorrhage (arrows), hyalinization (arrowheads), and extensive infiltration of inflammatory cells in both alveolar space and lung parenchyma are illustrated. (H) Survival rate. **P < 0.01, both infected groups (n = 10 for each) vs. controls (n = 6); and MHV-IAV (n = 10) vs. Veh-IAV (n = 10). (I) Weight was expressed as percentage of original weight. **P < 0.01, among MHV-IAV (n = 10), Veh-IAV (n = 10), and controls (n = 6). (J) Clinical scores on day 9 p.i. **P < 0.01, Veh-IAV vs. MHV-IAV, and both Veh-IAV and MHV-IAV vs. Veh-Veh. n = 5 for each group. (K–N) lung histology. K (10×) and L (40×), representative from MHV-IAV–infected mice; M (10×) and N (40×), representative from IAV-infected mice. Hemorrhage (arrows) and extensive infiltration of inflammatory cells (N) in both alveolar space and lung parenchyma are illustrated. Modest amounts of congestion and inflammatory infiltration in the alveolar septum was found in mice with MHV-IAV infections (thin arrow). Data are from at least 2 independent experiments. IN, intranasal; Inf Mon, inflammatory monocytes.