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Article: Alveolar macrophages protect mice from MERS-CoV-induced pneumonia and severe disease

Channappanavar, Rudragouda / Selvaraj, Muneeswaran / More, Sunil / Perlman, Stanley

Veterinary pathology. 2022 July, v. 59, no. 4

2022

Abstract: Emerging and re-emerging human coronaviruses (hCoVs) cause severe respiratory illness in humans, but the basis for lethal pneumonia in these diseases is not well understood. Alveolar macrophages (AMs) are key orchestrators of host antiviral defense and ... ...

Abstract	Emerging and re-emerging human coronaviruses (hCoVs) cause severe respiratory illness in humans, but the basis for lethal pneumonia in these diseases is not well understood. Alveolar macrophages (AMs) are key orchestrators of host antiviral defense and tissue tolerance during a variety of respiratory infections, and AM dysfunction is associated with severe COVID-19. In this study, using a mouse model of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, we examined the role of AMs in MERS pathogenesis. Our results show that depletion of AMs using clodronate (CL) liposomes significantly increased morbidity and mortality in human dipeptidyl peptidase 4 knock-in (hDPP4-KI) mice. Detailed examination of control and AM-depleted lungs at different days postinfection revealed increased neutrophil activity but a significantly reduced MERS-CoV-specific CD4 T-cell response in AM-deficient lungs during later stages of infection. Furthermore, enhanced MERS severity in AM-depleted mice correlated with lung inflammation and lesions. Collectively, these data demonstrate that AMs are critical for the development of an optimal virus-specific T-cell response and controlling excessive inflammation during MERS-CoV infection.
Keywords	CD4-positive T-lymphocytes ; COVID-19 infection ; Middle East respiratory syndrome coronavirus ; animal pathology ; disease severity ; humans ; inflammation ; lungs ; macrophages ; mice ; morbidity ; mortality ; neutrophils ; pathogenesis ; pneumonia
Language	English
Dates of publication	2022-07
Size	p. 627-638.
Publishing place	SAGE Publications
Document type	Article
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/03009858221095270
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Alveolar macrophages protect mice from MERS-CoV-induced pneumonia and severe disease.

Channappanavar, Rudragouda / Selvaraj, Muneeswaran / More, Sunil / Perlman, Stanley

Veterinary pathology

2022 Volume 59, Issue 4, Page(s) 627–638

Abstract	Emerging and re-emerging human coronaviruses (hCoVs) cause severe respiratory illness in humans, but the basis for lethal pneumonia in these diseases is not well understood. Alveolar macrophages (AMs) are key orchestrators of host antiviral defense and tissue tolerance during a variety of respiratory infections, and AM dysfunction is associated with severe COVID-19. In this study, using a mouse model of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, we examined the role of AMs in MERS pathogenesis. Our results show that depletion of AMs using clodronate (CL) liposomes significantly increased morbidity and mortality in human dipeptidyl peptidase 4 knock-in (hDPP4-KI) mice. Detailed examination of control and AM-depleted lungs at different days postinfection revealed increased neutrophil activity but a significantly reduced MERS-CoV-specific CD4 T-cell response in AM-deficient lungs during later stages of infection. Furthermore, enhanced MERS severity in AM-depleted mice correlated with lung inflammation and lesions. Collectively, these data demonstrate that AMs are critical for the development of an optimal virus-specific T-cell response and controlling excessive inflammation during MERS-CoV infection.
MeSH term(s)	Animals ; Clodronic Acid ; Coronavirus Infections/immunology ; Macrophages, Alveolar/immunology ; Mice ; Mice, Transgenic ; Middle East Respiratory Syndrome Coronavirus ; Pneumonia/immunology ; Pneumonia/virology
Chemical Substances	Clodronic Acid (0813BZ6866)
Language	English
Publishing date	2022-05-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1177/03009858221095270
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Exchange of C-Terminal Variable Sequences within Morbillivirus Nucleocapsid Protein Are Tolerated: Development and Evaluation of Two Marker (DIVA) Vaccines (Sungri/96 DIVA, Nigeria/75/1 DIVA) against PPR

Selvaraj, Muneeswaran / Mahapatra, Mana / Parida, Satya

Viruses. 2021 Nov. 21, v. 13, no. 11

2021

Abstract: Across Africa, the Middle East, and Asia, peste des petits ruminants virus (PPRV) places a huge disease burden on agriculture, affecting, in particular, small ruminant production. The recent PPR outbreaks in Northern Africa, the European part of Turkey, ... ...

Abstract	Across Africa, the Middle East, and Asia, peste des petits ruminants virus (PPRV) places a huge disease burden on agriculture, affecting, in particular, small ruminant production. The recent PPR outbreaks in Northern Africa, the European part of Turkey, and Bulgaria represent a significant threat to mainland Europe, as a source of disease. Although two safe and efficacious live attenuated vaccines (Sungri/96 and Nigeria/75/1) are available for the control of PPR, current serological tests do not enable the differentiation between naturally infected and vaccinated animals (DIVA). The vaccinated animals develop a full range of immune responses to viral proteins and, therefore, cannot be distinguished serologically from those that have recovered from a natural infection. This poses a serious problem for the post-vaccinal sero-surveillance during the ongoing PPR eradication program. Furthermore, during the latter stages of any eradication program, vaccination is only possible if the vaccine used is fully DIVA compliant. Using reverse genetics, we have developed two live attenuated PPR DIVA vaccines (Sungri/96 DIVA and Nigeria/75/1 DIVA), in which the C-terminal variable region of the PPRV N-protein has been replaced with dolphin morbillivirus (DMV). As a proof of principle, both the DIVA vaccines were evaluated in goats in pilot studies for safety and efficacy, and all the animals were clinically protected against the intranasal virulent virus challenge, similar to the parent vaccines. Furthermore, it is possible to differentiate between infected animals and vaccinated animals using two newly developed ELISAs. Therefore, these DIVA vaccines and associated tests can facilitate the sero-monitoring process and speed up the implementation of global PPR eradication through vaccination.
Keywords	burden of disease ; dolphins ; live vaccines ; nucleocapsid proteins ; reverse genetics ; vaccination ; virulence ; viruses ; Bulgaria ; Middle East ; Northern Africa
Language	English
Dates of publication	2021-1121
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13112320
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Exchange of C-Terminal Variable Sequences within Morbillivirus Nucleocapsid Protein Are Tolerated: Development and Evaluation of Two Marker (DIVA) Vaccines (Sungri/96 DIVA, Nigeria/75/1 DIVA) against PPR.

Selvaraj, Muneeswaran / Mahapatra, Mana / Parida, Satya

Viruses

2021 Volume 13, Issue 11

Abstract	Across Africa, the Middle East, and Asia, peste des petits ruminants virus (PPRV) places a huge disease burden on agriculture, affecting, in particular, small ruminant production. The recent PPR outbreaks in Northern Africa, the European part of Turkey, and Bulgaria represent a significant threat to mainland Europe, as a source of disease. Although two safe and efficacious live attenuated vaccines (Sungri/96 and Nigeria/75/1) are available for the control of PPR, current serological tests do not enable the differentiation between naturally infected and vaccinated animals (DIVA). The vaccinated animals develop a full range of immune responses to viral proteins and, therefore, cannot be distinguished serologically from those that have recovered from a natural infection. This poses a serious problem for the post-vaccinal sero-surveillance during the ongoing PPR eradication program. Furthermore, during the latter stages of any eradication program, vaccination is only possible if the vaccine used is fully DIVA compliant. Using reverse genetics, we have developed two live attenuated PPR DIVA vaccines (Sungri/96 DIVA and Nigeria/75/1 DIVA), in which the C-terminal variable region of the PPRV N-protein has been replaced with dolphin morbillivirus (DMV). As a proof of principle, both the DIVA vaccines were evaluated in goats in pilot studies for safety and efficacy, and all the animals were clinically protected against the intranasal virulent virus challenge, similar to the parent vaccines. Furthermore, it is possible to differentiate between infected animals and vaccinated animals using two newly developed ELISAs. Therefore, these DIVA vaccines and associated tests can facilitate the sero-monitoring process and speed up the implementation of global PPR eradication through vaccination.
MeSH term(s)	Animal Diseases/immunology ; Animal Diseases/prevention & control ; Animal Diseases/virology ; Animals ; Peste-des-Petits-Ruminants/immunology ; Peste-des-Petits-Ruminants/prevention & control ; Peste-des-Petits-Ruminants/virology ; Peste-des-petits-ruminants virus/immunology ; Ruminants/virology ; Vaccination/veterinary ; Viral Vaccines/immunology
Chemical Substances	Viral Vaccines
Language	English
Publishing date	2021-11-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13112320
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The SARS-CoV-2 neutralizing antibody response to SD1 and its evasion by BA.2.86.

Zhou, Daming / Supasa, Piyada / Liu, Chang / Dijokaite-Guraliuc, Aiste / Duyvesteyn, Helen M E / Selvaraj, Muneeswaran / Mentzer, Alexander J / Das, Raksha / Dejnirattisai, Wanwisa / Temperton, Nigel / Klenerman, Paul / Dunachie, Susanna J / Fry, Elizabeth E / Mongkolsapaya, Juthathip / Ren, Jingshan / Stuart, David I / Screaton, Gavin R

Nature communications

2024 Volume 15, Issue 1, Page(s) 2734

Abstract: Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to the failure of all mAbs developed for clinical use. Most potent antibodies bind to the ... ...

Abstract	Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to the failure of all mAbs developed for clinical use. Most potent antibodies bind to the receptor binding domain which has become heavily mutated. Here we study responses to a conserved epitope in sub-domain-1 (SD1) of spike which have become more prominent because of mutational escape from antibodies directed to the receptor binding domain. Some SD1 reactive mAbs show potent and broad neutralization of SARS-CoV-2 variants. We structurally map the dominant SD1 epitope and provide a mechanism of action by blocking interaction with ACE2. Mutations in SD1 have not been sustained to date, but one, E554K, leads to escape from mAbs. This mutation has now emerged in several sublineages including BA.2.86, reflecting selection pressure on the virus exerted by the increasing prominence of the anti-SD1 response.
MeSH term(s)	Humans ; Antibodies, Neutralizing ; SARS-CoV-2/genetics ; COVID-19 ; Antibodies, Monoclonal ; Epitopes ; Spike Glycoprotein, Coronavirus/genetics ; Antibodies, Viral ; Syndactyly
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Monoclonal ; Epitopes ; Spike Glycoprotein, Coronavirus ; Antibodies, Viral ; spike protein, SARS-CoV-2
Language	English
Publishing date	2024-03-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46982-6
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Rapid Detection of Peste des Petits Ruminants Virus (PPRV) Nucleic Acid Using a Novel Low-Cost Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) Assay for Future Use in Nascent PPR Eradication Programme

Mahapatra, Mana / Howson, Emma / Fowler, Veronica / Batten, Carrie / Flannery, John / Selvaraj, Muneeswaran / Parida, Satya

Viruses. 2019 July 31, v. 11, no. 8

2019

Abstract: Peste des petits ruminants (PPR) is a disease of small ruminants caused by peste des petits ruminants virus (PPRV), and is endemic in Asia, the Middle East and Africa. Effective control combines the application of early warning systems, accurate ... ...

Abstract	Peste des petits ruminants (PPR) is a disease of small ruminants caused by peste des petits ruminants virus (PPRV), and is endemic in Asia, the Middle East and Africa. Effective control combines the application of early warning systems, accurate laboratory diagnosis and reporting, animal movement restrictions, suitable vaccination and surveillance programs, and the coordination of all these measures by efficient veterinary services. Molecular assays, including conventional reverse transcription-polymerase chain reaction (RT-PCR) and real-time RT-PCR (RT-qPCR) have improved the sensitivity and rapidity of diagnosing PPR. However, currently these assays are only performed within laboratory settings; therefore, the development of field diagnostics for PPR would improve the fast implementation of control policies, particularly when PPR has been targeted to be eradicated by 2030. Loop-mediated isothermal amplification (LAMP) assays are simple to use, rapid, and have sensitivity and specificity within the range of RT-qPCR; and can be performed in the field using disposable consumables and portable equipment. This study describes the development of a novel RT-LAMP assay for the detection of PPRV nucleic acid by targeting the N-protein gene. The RT-LAMP assay was evaluated using cell culture propagated PPRVs, field samples from clinically infected animals and samples from experimentally infected animals encompassing all four lineages (I-IV) of PPRV. The test displayed 100% concordance with RT-qPCR when considering an RT-qPCR cut-off value of C<inf>T</inf> >40. Further, the RT-LAMP assay was evaluated using experimental and outbreak samples without prior RNA extraction making it more time and cost-effective. This assay provides a solution for a pen-side, rapid and inexpensive PPR diagnostic for use in the field in nascent PPR eradication programme.
Keywords	RNA ; Small ruminant morbillivirus ; animal diseases ; cell culture ; cost effectiveness ; diagnostic techniques ; early warning systems ; genes ; issues and policy ; laboratory diagnosis ; monitoring ; peste des petits ruminants ; portable equipment ; quantitative polymerase chain reaction ; rapid methods ; reverse transcriptase polymerase chain reaction ; reverse transcription loop-mediated isothermal amplification ; small ruminants ; transcription (genetics) ; vaccination ; veterinary services
Language	English
Dates of publication	2019-0731
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v11080699
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Rapid Detection of Peste des Petits Ruminants Virus (PPRV) Nucleic Acid Using a Novel Low-Cost Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) Assay for Future Use in Nascent PPR Eradication Programme.

Mahapatra, Mana / Howson, Emma / Fowler, Veronica / Batten, Carrie / Flannery, John / Selvaraj, Muneeswaran / Parida, Satya

Viruses

2019 Volume 11, Issue 8

Abstract	Peste des petits ruminants (PPR) is a disease of small ruminants caused by peste des petits ruminants virus (PPRV), and is endemic in Asia, the Middle East and Africa. Effective control combines the application of early warning systems, accurate laboratory diagnosis and reporting, animal movement restrictions, suitable vaccination and surveillance programs, and the coordination of all these measures by efficient veterinary services. Molecular assays, including conventional reverse transcription-polymerase chain reaction (RT-PCR) and real-time RT-PCR (RT-qPCR) have improved the sensitivity and rapidity of diagnosing PPR. However, currently these assays are only performed within laboratory settings; therefore, the development of field diagnostics for PPR would improve the fast implementation of control policies, particularly when PPR has been targeted to be eradicated by 2030. Loop-mediated isothermal amplification (LAMP) assays are simple to use, rapid, and have sensitivity and specificity within the range of RT-qPCR; and can be performed in the field using disposable consumables and portable equipment. This study describes the development of a novel RT-LAMP assay for the detection of PPRV nucleic acid by targeting the N-protein gene. The RT-LAMP assay was evaluated using cell culture propagated PPRVs, field samples from clinically infected animals and samples from experimentally infected animals encompassing all four lineages (I-IV) of PPRV. The test displayed 100% concordance with RT-qPCR when considering an RT-qPCR cut-off value of C
MeSH term(s)	Animals ; DNA Primers/genetics ; DNA, Viral/isolation & purification ; Disease Outbreaks/prevention & control ; Disease Outbreaks/veterinary ; Eye/virology ; Goat Diseases/diagnosis ; Goat Diseases/virology ; Goats/virology ; Nose/virology ; Nucleic Acid Amplification Techniques/methods ; Nucleocapsid Proteins/genetics ; Pathology, Molecular/methods ; Peste-des-Petits-Ruminants/blood ; Peste-des-Petits-Ruminants/diagnosis ; Peste-des-petits-ruminants virus/isolation & purification ; Reverse Transcription ; Sensitivity and Specificity ; Sheep ; Sheep Diseases/diagnosis ; Temperature
Chemical Substances	DNA Primers ; DNA, Viral ; Nucleocapsid Proteins
Language	English
Publishing date	2019-07-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v11080699
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Emerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection.

Nature communications

2024 Volume 15, Issue 1, Page(s) 3284

Abstract: The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through ... ...

Abstract	The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. Twenty eight potent antibodies are isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5, SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of BA.4/5 mAbs culminating in total loss of function with recent XBB.1.5.70 variants containing the so-called 'FLip' mutations at positions 455 and 456. Interestingly, activity of some mAbs is regained on the recently reported variant BA.2.86.
MeSH term(s)	Humans ; Antibodies, Monoclonal ; Mutation ; Postoperative Complications ; SARS-CoV-2/genetics ; Antibodies, Neutralizing ; Antibodies, Viral
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antibodies, Viral
Language	English
Publishing date	2024-04-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47393-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Time-Dependent Increase in Susceptibility and Severity of Secondary Bacterial Infections During SARS-CoV-2.

Smith, Amanda P / Williams, Evan P / Plunkett, Taylor R / Selvaraj, Muneeswaran / Lane, Lindey C / Zalduondo, Lillian / Xue, Yi / Vogel, Peter / Channappanavar, Rudragouda / Jonsson, Colleen B / Smith, Amber M

Frontiers in immunology

2022 Volume 13, Page(s) 894534

Abstract: Secondary bacterial infections can exacerbate SARS-CoV-2 infection, but their prevalence and impact remain poorly understood. Here, we established that a mild to moderate infection with the SARS-CoV-2 USA-WA1/2020 strain increased the risk of ... ...

Abstract	Secondary bacterial infections can exacerbate SARS-CoV-2 infection, but their prevalence and impact remain poorly understood. Here, we established that a mild to moderate infection with the SARS-CoV-2 USA-WA1/2020 strain increased the risk of pneumococcal (type 2 strain D39) coinfection in a time-dependent, but sex-independent, manner in the transgenic K18-hACE2 mouse model of COVID-19. Bacterial coinfection increased lethality when the bacteria was initiated at 5 or 7 d post-virus infection (pvi) but not at 3 d pvi. Bacterial outgrowth was accompanied by neutrophilia in the groups coinfected at 7 d pvi and reductions in B cells, T cells, IL-6, IL-15, IL-18, and LIF were present in groups coinfected at 5 d pvi. However, viral burden, lung pathology, cytokines, chemokines, and immune cell activation were largely unchanged after bacterial coinfection. Examining surviving animals more than a week after infection resolution suggested that immune cell activation remained high and was exacerbated in the lungs of coinfected animals compared with SARS-CoV-2 infection alone. These data suggest that SARS-CoV-2 increases susceptibility and pathogenicity to bacterial coinfection, and further studies are needed to understand and combat disease associated with bacterial pneumonia in COVID-19 patients.
MeSH term(s)	Animals ; Bacteria ; Bacterial Infections ; COVID-19 ; Coinfection ; Humans ; Mice ; Mice, Transgenic ; SARS-CoV-2
Language	English
Publishing date	2022-05-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.894534
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Article: Time-Dependent Increase in Susceptibility and Severity of Secondary Bacterial Infection during SARS-CoV-2 Infection.

bioRxiv : the preprint server for biology

2022

Abstract: Secondary bacterial infections can exacerbate SARS-CoV-2 infection, but their prevalence and impact remain poorly understood. Here, we established that a mild to moderate SARS-CoV-2 infection increased the risk of pneumococcal coinfection in a time- ... ...

Abstract	Secondary bacterial infections can exacerbate SARS-CoV-2 infection, but their prevalence and impact remain poorly understood. Here, we established that a mild to moderate SARS-CoV-2 infection increased the risk of pneumococcal coinfection in a time-dependent, but sexindependent, manner in the transgenic K18-hACE mouse model of COVID-19. Bacterial coinfection was not established at 3 d post-virus, but increased lethality was observed when the bacteria was initiated at 5 or 7 d post-virus infection (pvi). Bacterial outgrowth was accompanied by neutrophilia in the groups coinfected at 7 d pvi and reductions in B cells, T cells, IL-6, IL-15, IL-18, and LIF were present in groups coinfected at 5 d pvi. However, viral burden, lung pathology, cytokines, chemokines, and immune cell activation were largely unchanged after bacterial coinfection. Examining surviving animals more than a week after infection resolution suggested that immune cell activation remained high and was exacerbated in the lungs of coinfected animals compared with SARS-CoV-2 infection alone. These data suggest that SARS-CoV-2 increases susceptibility and pathogenicity to bacterial coinfection, and further studies are needed to understand and combat disease associated with bacterial pneumonia in COVID-19 patients.
Language	English
Publishing date	2022-03-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.02.28.482305
Database	MEDical Literature Analysis and Retrieval System OnLINE

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