Heat-killed Lactobacillus casei confers broad protection against influenza A virus primary infection and develops heterosubtypic immunity against future secondary infection

Jung, Yu Jin; Lee, Young Tae; Ngo, Vu L.; Cho, Young Hee; Ko, Eun Ju; Hong, Sup; Kim, Ki Hye; Jang, Ji Hun; Oh, Joon Suk; Park, Min Kyung; Kim, Cheol Hyun; Sun, Jun; Kang, Sang-Moo

doi:10.1038/s41598-017-17487-8

Cited by 100 publications

(78 citation statements)

References 49 publications

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“…As described above, bacterial pathogens given prior to influenza viruses can stimulate innate immunity that reduces the severity of influenza (56,58). Infection of mice with nonpathogenic bacteria or with a parasite that causes a chronic infection has also been shown to reduce the severity of influenza infections (34,(62)(63)(64)(65). While the mechanisms of protection may differ among coinfecting microbes, protection relies on detection of the initial infection by pattern recognition receptors.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

González

Ijezie

Balemba

et al. 2018

J Virol

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Influenza viruses and rhinoviruses are responsible for a large number of acute respiratory viral infections in human populations and are detected as copathogens within hosts. Clinical and epidemiological studies suggest that coinfection by rhinovirus and influenza virus may reduce disease severity and that they may also interfere with each other's spread within a host population. To determine how coinfection by these two unrelated respiratory viruses affects pathogenesis, we established a mouse model using a minor serogroup rhinovirus (rhinovirus strain 1B [RV1B]) and mouse-adapted influenza A virus (A/Puerto Rico/8/1934 [PR8]). Infection of mice with RV1B 2 days before PR8 reduced the severity of infection by a low or medium, but not high, dose of PR8. Disease attenuation was associated with an early inflammatory response in the lungs and enhanced clearance of PR8. However, coinfection by RV1B did not reduce PR8 viral loads early in infection or inhibit replication of PR8 within respiratory epithelia or Inflammation in coinfected mice remained focal compared to diffuse inflammation and damage in the lungs of mice infected by PR8. The timing of RV1B coinfection was a critical determinant of protection, suggesting that sufficient time is needed to induce this response. Finally, disease attenuation was not unique to RV1B: dose-dependent coinfection by a murine coronavirus (mouse hepatitis virus strain 1 [MHV-1]) also reduced the severity of PR8 infection. Unlike RV1B, coinfection with MHV-1 reduced early PR8 replication, which was associated with upregulation of beta interferon (IFN-β) expression. This model is critical for understanding the mechanisms responsible for influenza disease attenuation during coinfection by unrelated respiratory viruses. Viral infections in the respiratory tract can cause severe disease and are responsible for a majority of pediatric hospitalizations. Molecular diagnostics have revealed that approximately 20% of these patients are infected by more than one unrelated viral pathogen. To understand how viral coinfection affects disease severity, we inoculated mice with a mild viral pathogen (rhinovirus or murine coronavirus), followed 2 days later by a virulent viral pathogen (influenza A virus). This model demonstrated that rhinovirus can reduce the severity of influenza A virus, which corresponded with an early but controlled inflammatory response in the lungs and early clearance of influenza A virus. We further determined the dose and timing parameters that were important for effective disease attenuation and showed that influenza disease is also reduced by coinfection with a murine coronavirus. These findings demonstrate that coinfecting viruses can alter immune responses and pathogenesis in the respiratory tract.

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Section: Discussionmentioning

confidence: 99%

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

González

Ijezie

Balemba

et al. 2018

J Virol

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“…A closer evaluation of the role of AMs as both an independent source and a target of IL-6 in both pneumovirus and influenza infections might help to explain some of these divergent responses. It is also intriguing to note that the lethal sequelae influenza A can be limited by Lactobacillus at the respiratory mucosa (16)(17)(18)(19), results that suggest that AMs and IL-6 are not unique or universal targets of this immunomodulatory strategy.…”

Section: Discussionmentioning

confidence: 99%

“…14). Toward this end, we and others have found that administration of otherwise benign Lactobacillus species directly to the respiratory mucosa of virusinfected mice has resulted in protection against lethal disease (15)(16)(17)(18)(19). The mechanisms underlying this response and, more broadly, the ways in which bacteria, bacterial components, and pattern recognition receptor-activating ligands administered to the respiratory tract promote protection against lethal virus infection remain to be fully elucidated (20)(21)(22).…”

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confidence: 99%

Critical Adverse Impact of IL-6 in Acute Pneumovirus Infection

Percopo

Brenner

et al. 2019

The Journal of Immunology

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C.M.P. designed and performed experiments and reviewed first and subsequent drafts of the manuscript; M.M. performed experiments for the revised manuscript, assessed experimental outcomes, evaluated data for publication, and reviewed first and subsequent drafts of the manuscript; T.A.B. designed and performed experiments and reviewed first and subsequent drafts of the manuscript; J.O.K. designed and performed experiments involving infection with rK2-PVM and reviewed first and subsequent drafts of the manuscript; T.J.B. provided critical assistance in designing flow cytometric protocols and reviewed first and subsequent drafts of the manuscript; K.L. provided critical assistance for evaluation of T cells and T cell subsets and reviewed manuscript revision prior to publication; H.F.R. conceptualized the study, performed experiments, evaluated data, and generated the first and subsequent drafts of the written manuscript.

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“…The amounts of ginseng samples in the mixtures were in the range of 50–1000 µg doses per mouse. Then, 50 µL of virus–ginseng mixtures were intranasally inoculated into naive mice [ 19 , 20 ]. For the experiment involving treatment with ginseng after infection, wild-type BALB/c mice were infected with A/WSN (H1N1) influenza virus (1 × LD 50 ) first.…”

Section: Methodsmentioning

confidence: 99%

Antiviral Activity of Fermented Ginseng Extracts against a Broad Range of Influenza Viruses

Wang

Jung

Kim

et al. 2018

Viruses

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Ginseng products used as herb nutritional supplements are orally consumed and fermented to ginsenoside compounds by the intestinal microbes. In this study, we investigated antiviral protective effects of fermented ginseng extracts against different strains of influenza viruses in genetically diverse mouse models. Intranasal coinoculation of mice with fermented ginseng extract and influenza virus improved survival rates and conferred protection against H1N1, H3N2, H5N1, and H7N9 strains, with the efficacy dependent on the dose of ginseng samples. Antiviral protection by fermented ginseng extract was observed in different genetic backgrounds of mice and in the deficient conditions of key adaptive immune components (CD4, CD8, B cell, MHCII). The mice that survived primary virus inoculation with fermented ginseng extract developed immunity against the secondary infection with homologous and heterosubtypic viruses. In vitro cell culture experiments showed moderate virus neutralizing activity by fermented ginseng extract, probably by inhibiting hemagglutination and neuraminidase activity. This study suggests that fermented ginseng extracts might provide a means to treat influenza disease regardless of virus strains.

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Heat-killed Lactobacillus casei confers broad protection against influenza A virus primary infection and develops heterosubtypic immunity against future secondary infection

Cited by 100 publications

References 49 publications

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

Critical Adverse Impact of IL-6 in Acute Pneumovirus Infection

Antiviral Activity of Fermented Ginseng Extracts against a Broad Range of Influenza Viruses

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