Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody

Katherine V. Houser, Andrew J. Broadbent, Lisa Gretebeck, Leatrice Vogel, Elaine W. Lamirande, Troy Sutton, Kevin W. Bock, Mahnaz Minai, Marlene Orandle, Ian N. Moore, Kanta Subbarao

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that was first detected in humans in 2012 as a cause of severe acute respiratory disease. As of July 28, 2017, there have been 2,040 confirmed cases with 712 reported deaths. While many infections have been fatal, there have also been a large number of mild or asymptomatic cases discovered through monitoring and contact tracing. New Zealand white rabbits are a possible model for asymptomatic infection with MERS-CoV. In order to discover more about non-lethal infections and to learn whether a single infection with MERS-CoV would protect against reinfection, we inoculated rabbits with MERS-CoV and monitored the antibody and inflammatory response. Following intranasal infection, rabbits developed a transient dose-dependent pulmonary infection with moderately high levels of viral RNA, viral antigen, and perivascular inflammation in multiple lung lobes that was not associated with clinical signs. The rabbits developed antibodies against viral proteins that lacked neutralizing activity and the animals were not protected from reinfection. In fact, reinfection resulted in enhanced pulmonary inflammation, without an associated increase in viral RNA titers. Interestingly, passive transfer of serum from previously infected rabbits to naïve rabbits was associated with enhanced inflammation upon infection. We further found this inflammation was accompanied by increased recruitment of complement proteins compared to primary infection. However, reinfection elicited neutralizing antibodies that protected rabbits from subsequent viral challenge. Our data from the rabbit model suggests that people exposed to MERS-CoV who fail to develop a neutralizing antibody response, or persons whose neutralizing antibody titers have waned, may be at risk for severe lung disease on re-exposure to MERS-CoV.

Original languageEnglish (US)
Article numbere1006565
JournalPLoS pathogens
Volume13
Issue number8
DOIs
StatePublished - Aug 2017

Fingerprint

Neutralizing Antibodies
Rabbits
Inflammation
Infection
Viral RNA
Antibody Formation
Contact Tracing
Lung
Asymptomatic Infections
Middle East Respiratory Syndrome Coronavirus
Viral Antigens
Zoonoses
Viral Proteins
Acute Disease
Lung Diseases
Pneumonia
Complement System Proteins
Antibodies
Serum

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Houser, Katherine V. ; Broadbent, Andrew J. ; Gretebeck, Lisa ; Vogel, Leatrice ; Lamirande, Elaine W. ; Sutton, Troy ; Bock, Kevin W. ; Minai, Mahnaz ; Orandle, Marlene ; Moore, Ian N. ; Subbarao, Kanta. / Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody. In: PLoS pathogens. 2017 ; Vol. 13, No. 8.
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abstract = "The Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that was first detected in humans in 2012 as a cause of severe acute respiratory disease. As of July 28, 2017, there have been 2,040 confirmed cases with 712 reported deaths. While many infections have been fatal, there have also been a large number of mild or asymptomatic cases discovered through monitoring and contact tracing. New Zealand white rabbits are a possible model for asymptomatic infection with MERS-CoV. In order to discover more about non-lethal infections and to learn whether a single infection with MERS-CoV would protect against reinfection, we inoculated rabbits with MERS-CoV and monitored the antibody and inflammatory response. Following intranasal infection, rabbits developed a transient dose-dependent pulmonary infection with moderately high levels of viral RNA, viral antigen, and perivascular inflammation in multiple lung lobes that was not associated with clinical signs. The rabbits developed antibodies against viral proteins that lacked neutralizing activity and the animals were not protected from reinfection. In fact, reinfection resulted in enhanced pulmonary inflammation, without an associated increase in viral RNA titers. Interestingly, passive transfer of serum from previously infected rabbits to na{\"i}ve rabbits was associated with enhanced inflammation upon infection. We further found this inflammation was accompanied by increased recruitment of complement proteins compared to primary infection. However, reinfection elicited neutralizing antibodies that protected rabbits from subsequent viral challenge. Our data from the rabbit model suggests that people exposed to MERS-CoV who fail to develop a neutralizing antibody response, or persons whose neutralizing antibody titers have waned, may be at risk for severe lung disease on re-exposure to MERS-CoV.",
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Houser, KV, Broadbent, AJ, Gretebeck, L, Vogel, L, Lamirande, EW, Sutton, T, Bock, KW, Minai, M, Orandle, M, Moore, IN & Subbarao, K 2017, 'Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody', PLoS pathogens, vol. 13, no. 8, e1006565. https://doi.org/10.1371/journal.ppat.1006565

Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody. / Houser, Katherine V.; Broadbent, Andrew J.; Gretebeck, Lisa; Vogel, Leatrice; Lamirande, Elaine W.; Sutton, Troy; Bock, Kevin W.; Minai, Mahnaz; Orandle, Marlene; Moore, Ian N.; Subbarao, Kanta.

In: PLoS pathogens, Vol. 13, No. 8, e1006565, 08.2017.

Research output: Contribution to journalArticle

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AU - Houser, Katherine V.

AU - Broadbent, Andrew J.

AU - Gretebeck, Lisa

AU - Vogel, Leatrice

AU - Lamirande, Elaine W.

AU - Sutton, Troy

AU - Bock, Kevin W.

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AU - Subbarao, Kanta

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