Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

Schmidt, Megan E.; Varga, Steven M.

doi:10.1016/j.cyto.2018.07.012

Cited by 37 publications

(28 citation statements)

References 113 publications

(262 reference statements)

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“…3A, B). This depletion resulted in significantly reduced survival of SeV infection (Supplementary Figure 3C), compatible with the known antiviral functions of CD8 + T cells (34–36). However, it is notable that Pam2-ODN treatment still significantly enhanced survival of SeV challenge even in the absence of CD8 + T cells (Supplementary Figure 3C).…”

Section: Resultssupporting

confidence: 79%

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Immune modulation to improve survival of respiratory virus infections in mice

Wali

Gonzalez

Jaramillo

et al. 2020

Preprint

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Viral pneumonia remains a global health threat requiring novel treatment strategies, as strikingly exemplified in the SARS-CoV-2 pandemic of 2019-2020. We have reported that mice treated with a combination of inhaled Toll-like receptor (TLR) 2/6 and TLR 9 agonists (Pam2-ODN) to stimulate innate immunity are broadly protected against respiratory pathogens, but the mechanisms underlying this protection remain incompletely elucidated. Here, we show in a lethal paramyxovirus model that Pam2-ODN-enhanced survival is associated with robust virus inactivation by reactive oxygen species (ROS), which occurs prior to internalization by lung epithelial cells. However, we also found that mortality in sham-treated mice temporally corresponded with CD8+ T cell-enriched lung inflammation that peaks on days 11-12 after viral challenge, when the viral burden has waned to a scarcely detectable level. Pam2-ODN treatment blocked this injurious inflammation by reducing the viral burden, and alternatively, depleting CD8+ T cells 8 days after viral challenge also decreased mortality. These findings reveal opportunities for targeted immunomodulation to protect susceptible individuals against the morbidity and mortality of respiratory viral infections.

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Section: Resultssupporting

confidence: 79%

“…Previous reports support the concept of counter-balanced immune protection and immunopathology by CD8 + T cells during virus infections (36–41). Some reports have shown that antigen-experienced memory CD8 + T cells enhance respiratory syncytial virus (RSV) clearance, but also mediate severe immunopathology (39, 42).…”

Section: Discussionsupporting

confidence: 52%

Immune modulation to improve survival of respiratory virus infections in mice

Wali

Gonzalez

Jaramillo

et al. 2020

Preprint

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“…Previous reports support this concept of counter-balanced immune protection and immunopathology by CD8 + T cells during virus infections 24,28–32 . Some reports have shown that antigen-experienced memory CD8 + T cells enhance respiratory syncytial virus (RSV) clearance, but also mediate severe immunopathology 30,33 .…”

Section: Discussionmentioning

confidence: 71%

“…4). This was not surprising, given the known role of CD8 + T cells in virus clearance 24–28 . However, Pam2-ODN treatment still significantly enhanced survival of SeV challenge, even in the absence of CD8 + T cells (Fig.…”

Section: Resultsmentioning

confidence: 94%

Inducible epithelial resistance improves survival of Sendai virus pneumonia in mice by both inactivating virus and preventing CD8⁺T cell-mediated immunopathology

Wali

Flores²,

Jaramillo³

et al. 2020

Preprint

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17Viral pneumonias remain a global health threat necessitating novel strategies to prevent 18 and treat these lower respiratory tract infections. We have reported that mice treated 19 with a combination of inhaled Toll-like receptor (TLR) 2/6 and TLR 9 agonists (Pam2-20 2 ODN) are broadly protected against respiratory pathogens. Although a single inhalation 21 of Pam-ODN prevents acute morbidity and chronic complications associated with viral 22 pneumonias, the mechanisms underlying this protection remain incompletely elucidated. 23Here, we show in a lethal paramyxovirus model that Pam2-ODN-enhanced survival is 24 associated with robust virus inactivation that occurs prior to internalization by lung 25 epithelial cells. However, it was also noted that viral mortality in sham-treated mice 26 temporally corresponded with CD8 + T cell-enriched lung inflammation that peaks after 27 the viral burden wanes. Pam2-ODN treatment also blocked this injurious inflammation, 28 but the attenuation of lymphocytic inflammation and the reduction in virus burden were 29 both lost when inducible reactive oxygen species generation was inhibited. Depleting 30 CD8 + T cells before or after viral challenge underscored the balanced roles of CD8 + T 31 cells in antiviral immunity and fatal immunopathology, but did not obviate the Pam2-32 ODN antiviral protection. These findings identify multifunctional inducible antiviral 33 mechanisms and may reveal means to protect susceptible individuals against 34 respiratory infections. 35 36 42 3 development of novel therapeutic anti-viral strategies is required to effectively prevent 43 and treat respiratory infections and their associated chronic complications 8-10 . 44 While lung epithelial cells are the principal targets of most respiratory viruses, there is 45 expanding evidence that lung epithelia are capable of generating anti-microbial 46 responses 7,11 . We hypothesized that lung epithelial cells can be harnessed to control 47 virus replication, thereby enhancing acute survival and reducing chronic complications 48 of virus infections 12-15 . Our group has previously described the phenomenon of inducible 49 epithelial resistance wherein the lungs' mucosal defenses can be broadly stimulated to 50 protect against a wide range of respiratory pathogens, including viruses 12-17 . This 51 protection is induced by a single inhalation of a combination treatment consisting of Toll 52 like receptor (TLR) 2/6 and 9 agonists (Pam2-ODN) before or after viral challenge. 53 While no individual leukocyte populations have been identified as critical for Pam2-54 ODN-induced resistance, lung epithelial cells are essential to the inducible anti-viral 55 response 12 . Further, we have shown that Pam2-ODN mediated protection is dependent 56 upon epithelial generation of reactive oxygen species (ROS) but, interestingly, does not 57 require Type I interferons 16,17 . More recently, we have shown prevention of chronic 58 virus-induced asthma in mice treated with Pam2-ODN but we have not clarified the anti-59 vi...

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“…T cell responses are also important for protection against RSV. CD4 + T lymphocytes contribute to T-cell dependent antibody responses and indirectly to viral clearance (as evidenced by persistent infections in HIV-infected individuals) and CD8 + T lymphocytes clear the virus from infected cells (5, 19).…”

Section: Eliciting Protective Immunity Against Rsv Lrtimentioning

confidence: 99%

Prevention of Pediatric Respiratory Syncytial Virus Lower Respiratory Tract Illness: Perspectives for the Next Decade

Aranda

Polack

2019

Front. Immunol.

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The landscape of infant bronchiolitis and viral pneumonia may be altered by preventive interventions against respiratory syncytial virus under evaluation today. Pediatric wards in 2018 in developing countries may differ from those attended by future generation pediatricians who may not witness the packed emergency rooms, lack of available beds, or emergency situations that all physicians caring for children with RSV experience every year. In this review, we describe and discuss different prevention strategies under evaluation to protect pediatric patients. Then, we outline a number of potential challenges, benefits, and concerns that may result from successful interventions after licensure.

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Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

Cited by 37 publications

References 113 publications

Immune modulation to improve survival of respiratory virus infections in mice

Immune modulation to improve survival of respiratory virus infections in mice

Inducible epithelial resistance improves survival of Sendai virus pneumonia in mice by both inactivating virus and preventing CD8⁺T cell-mediated immunopathology

Prevention of Pediatric Respiratory Syncytial Virus Lower Respiratory Tract Illness: Perspectives for the Next Decade

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Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

Cited by 37 publications

References 113 publications

Immune modulation to improve survival of respiratory virus infections in mice

Immune modulation to improve survival of respiratory virus infections in mice

Inducible epithelial resistance improves survival of Sendai virus pneumonia in mice by both inactivating virus and preventing CD8+T cell-mediated immunopathology

Prevention of Pediatric Respiratory Syncytial Virus Lower Respiratory Tract Illness: Perspectives for the Next Decade

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Inducible epithelial resistance improves survival of Sendai virus pneumonia in mice by both inactivating virus and preventing CD8⁺T cell-mediated immunopathology