Subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques

SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8 + T-cell responses in convalescent individuals, the role of virus-specific CD8 + T-cell responses in the control of SARS-CoV-2 rep...

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Published inPLoS pathogens Vol. 17; no. 7; p. e1009668
Main Authors Nomura, Takushi, Yamamoto, Hiroyuki, Nishizawa, Masako, Hau, Trang Thi Thu, Harada, Shigeyoshi, Ishii, Hiroshi, Seki, Sayuri, Nakamura-Hoshi, Midori, Okazaki, Midori, Daigen, Sachie, Kawana-Tachikawa, Ai, Nagata, Noriyo, Iwata-Yoshikawa, Naoko, Shiwa, Nozomi, Iida, Shun, Katano, Harutaka, Suzuki, Tadaki, Park, Eun-Sil, Maeda, Ken, Suzaki, Yuriko, Ami, Yasushi, Matano, Tetsuro
Format Journal Article
LanguageEnglish
Published San Francisco Public Library of Science 19.07.2021
Public Library of Science (PLoS)
Subjects
Analysis
Animals
Antibodies
Biology and life sciences
CD8 antigen
Coronaviruses
COVID-19
Disease transmission
Experiments
Infections
Lymph nodes
Lymphocytes
Lymphocytes T
Medicine and health sciences
Mucosa
Necropsy
Pharynx
Replication
Respiratory failure
Ribonucleic acid
RNA
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
T cells
Viral diseases
Viral infections
Viruses
Japan
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Abstract SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8 + T-cell responses in convalescent individuals, the role of virus-specific CD8 + T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8 + T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 10 5 or 10 6 TCID 50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8 + T cells were undetectable on day 7 and thereafter, while virus-specific CD8 + T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10–17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8 + T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8 + T cells, implying that CD8 + T-cell dysfunction may not solely lead to viral control failure.
AbstractList SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8+ T-cell responses in convalescent individuals, the role of virus-specific CD8+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 105 or 106 TCID50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10-17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8+ T cells, implying that CD8+ T-cell dysfunction may not solely lead to viral control failure.SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8+ T-cell responses in convalescent individuals, the role of virus-specific CD8+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 105 or 106 TCID50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10-17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8+ T cells, implying that CD8+ T-cell dysfunction may not solely lead to viral control failure.
SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8.sup.+ T-cell responses in convalescent individuals, the role of virus-specific CD8.sup.+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8.sup.+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 10.sup.5 or 10.sup.6 TCID.sub.50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8.sup.+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8.sup.+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10-17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8.sup.+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8.sup.+ T cells, implying that CD8.sup.+ T-cell dysfunction may not solely lead to viral control failure.
SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8 + T-cell responses in convalescent individuals, the role of virus-specific CD8 + T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8 + T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 10 5 or 10 6 TCID 50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8 + T cells were undetectable on day 7 and thereafter, while virus-specific CD8 + T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10–17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8 + T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8 + T cells, implying that CD8 + T-cell dysfunction may not solely lead to viral control failure.
SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8 + T-cell responses in convalescent individuals, the role of virus-specific CD8 + T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8 + T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 10 5 or 10 6 TCID 50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8 + T cells were undetectable on day 7 and thereafter, while virus-specific CD8 + T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10–17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8 + T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8 + T cells, implying that CD8 + T-cell dysfunction may not solely lead to viral control failure. SARS-CoV-2 infection presents a wide spectrum of clinical manifestations ranging from asymptomatic to fatal respiratory failure. The determinants for failure in viral control and/or fatal disease progression have not been elucidated fully. Both acquired immune effectors, antibodies and CD8 + T cells, are considered to contribute to viral control. However, it remains unknown whether a deficiency in either of these two arms is directly linked to failure in the control of SARS-CoV-2 replication. In the present study, to know the requirement of CD8 + T cells for viral control after the establishment of infection, we examined the effect of CD8 + cell depletion by monoclonal anti-CD8 antibody administration in the subacute phase on SARS-CoV-2 replication in cynomolgus macaques. Unexpectedly, our analysis revealed no significant impact of CD8 + cell depletion on viral replication, indicating that subacute SARS-CoV-2 replication can be controlled in the absence of CD8 + T cells. CD8 + T-cell responses may contribute to viral control in SARS-CoV-2 infection, but this study suggests that CD8 + T-cell dysfunction may not solely lead to viral control failure or fatal disease progression.
SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8+ T-cell responses in convalescent individuals, the role of virus-specific CD8+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 105 or 106 TCID50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10–17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8+ T cells, implying that CD8+ T-cell dysfunction may not solely lead to viral control failure.
Audience Academic
Author Suzuki, Tadaki
Park, Eun-Sil
Nakamura-Hoshi, Midori
Okazaki, Midori
Seki, Sayuri
Ami, Yasushi
Ishii, Hiroshi
Katano, Harutaka
Nishizawa, Masako
Nagata, Noriyo
Shiwa, Nozomi
Iida, Shun
Yamamoto, Hiroyuki
Suzaki, Yuriko
Nomura, Takushi
Harada, Shigeyoshi
Iwata-Yoshikawa, Naoko
Daigen, Sachie
Hau, Trang Thi Thu
Kawana-Tachikawa, Ai
Matano, Tetsuro
Maeda, Ken
AuthorAffiliation 6 Management Department of Biosafety, Laboratory Animal, and Pathogen Bank, National Institute of Infectious Diseases, Tokyo, Japan
1 AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
2 Institute of Medical Science, University of Tokyo, Tokyo, Japan
3 Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
5 Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan
4 Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
Icahn School of Medicine at Mount Sinai, UNITED STATES
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Snippet SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional...
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SubjectTerms Analysis
Animals
Antibodies
Biology and life sciences
CD8 antigen
Coronaviruses
COVID-19
Disease transmission
Experiments
Infections
Lymph nodes
Lymphocytes
Lymphocytes T
Medicine and health sciences
Mucosa
Necropsy
Pharynx
Replication
Respiratory failure
Ribonucleic acid
RNA
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
T cells
Viral diseases
Viral infections
Viruses
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Title Subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques
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