Evaluation of nasal levels of interferon and clinical severity of influenza in children

Scottá, Marcelo Comerlato; Machado, Denise Pires; Oliveira, Suelen Goecks; Moura, Angela de; Estorgato, Geovana Rhoden; Souza, Ana Paula Duarte de; Porto, Bárbara Nery; Araújo, Patrícia Dias de; Sarria, Edgar E.; Pitrez, Paulo Márcio; Jones, Marcus Herbert; Pinto, Leonardo Araújo; Stein, Renato T.; Polack, Fernando P.; Mattiello, Rita

doi:10.1016/j.jcv.2019.02.003

Cited by 7 publications

(4 citation statements)

References 68 publications

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“…It is well known that two RSV nonstructural proteins, NS1 and NS2, as well as the envelope G glycoprotein, strongly suppress type I IFN production in RSV-infected cells (20,22,23). This is consistent with a clinical study that showed that RSV infection failed to induce a robust type I IFN response (24)(25)(26)(27). RSV infection elicits higher levels of the IFN lambda subtype (IFN-), which positively correlates with the severity of RSV bronchiolitis (28).…”

supporting

confidence: 82%

GBP5 Is an Interferon-Induced Inhibitor of Respiratory Syncytial Virus

Liu

et al. 2020

J Virol

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Guanylate binding protein 5 (GBP5) belongs to the guanosine triphosphatase (GTPase) subfamily, which is mainly induced by interferon γ (IFN-γ) and is involved in many important cellular processes, including inflammasome activation and innate immunity against a wide variety of microbial pathogens. However, it is unknown whether GBP5 inhibits respiratory syncytial virus (RSV) infection. Here, we identified GBP5 as an effector of the anti-RSV activity of IFN-γ and found that in children, the weaker immune response, especially the weaker IFN-γ response and the decreased GBP5 expression, leads to RSV susceptibility. Furthermore, we revealed that GBP5 reduced the cell-associated levels of the RSV small hydrophobic (SH) protein, which was identified as a viroporin. In contrast, overexpression of the SH protein rescued RSV replication in the presence of GBP5. The GBP5-induced decrease in intracellular SH protein levels is because GBP5 promotes the release of the SH protein into the cell culture. Moreover, the GBP5 C583A mutants at the C-terminus or lacking the C-terminus region, which impair GBP5 localisation in the Golgi, could not inhibit RSV infection, whereas the GTPase-defective GBP5 maintained RSV inhibition, suggesting that Golgi localisation but not the GTPase activity of GBP5 is required for RSV inhibition. Interestingly, we found that RSV infection or RSV G protein downregulates GBP5 expression by upregulating DZIP3, an E3 ligase, which induces GBP5 degradation through the K48-ubiquitination and proteasomal pathways. Thus, this study reveals a complicated interplay between host restrictive factor GBP5 and RSV infection and provides important information for understanding the pathogenesis of the RSV. IMPORTANCE RSV is a highly contagious virus that causes multiple infections in infants within their first year of life. It can also easily cause infection in elderly or immunocompromised individuals, suggesting that individual differences in immunity play an important role in RSV infection. Therefore, exploring the pathogenic mechanisms of RSV and identifying essential genes which inhibit RSV infection is necessary to develop an effective strategy to control RSV infection. In this study, we report that the IFN-inducible gene GBP5 potently inhibits RSV replication by reducing the cell-associated levels of the RSV small hydrophobic (SH) protein, which is a viroporin. In contrast, the RSV G protein was shown to upregulate the expression of the DZIP3 protein, an E3 ligase that degrades GBP5 through the proteasomal pathway. Our study provides important information for the understanding of the pathogenic mechanisms of RSV and host immunity as well as the complicated interplay between the virus and host.

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supporting

confidence: 82%

GBP5 Is an Interferon-Induced Inhibitor of Respiratory Syncytial Virus

Liu

et al. 2020

J Virol

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“…This result is consistent with results from the INFANT study, conducted by Argentine doctors to investigate the causes of respiratory diseases that seriously affect children such as RSV associated asthma and bronchiolitis, and pneumonia and influenza virus infection. In the INFANT study, RSV infection failed to induce a robust type I IFN response in the nasal mucosa of infants even when co-infected with influenza, which normally induces a robust response (70). Intriguingly, neonatal mouse models of RSV infection recapitulate these data from humans.…”

Section: Introductionmentioning

confidence: 99%

Role of Type I Interferon (IFN) in the Respiratory Syncytial Virus (RSV) Immune Response and Disease Severity

et al. 2019

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Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in children <2 years of age. Increased morbidity and mortality have been reported in high-risk patients, such as premature infants, patients with cardiac disease, and severely immune compromised patients. Severe disease is associated with the virulence of the virus as well as host factors specifically including the innate immune response. The role of type I interferons (IFNs) in the response to RSV infection is important in regulating the rate of virus clearance and in directing the character of the immune response, which is normally associated with protection and less severe disease. Two RSV non-structural proteins, NS1 and NS2, as well as the envelope G glycoprotein are known to suppress type I IFN production and a robust type I IFN response to RSV does not occur in human infants or neonatal mouse models of RSV infection. Additionally, presence of type I IFNs are associated with mild symptoms in infants and administration of IFN-α prior to infection of neonatal mice with RSV reduces immunopathology. This evidence has driven RSV prophylaxis and therapeutic efforts to consider strategies for enhancing type I IFN production.

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“…However, IFNα treatment is generally safe with appropriate caution and monitoring of potential toxicity [ 105 , 108 , 109 ]. The IFN response of the host undoubtedly influences RSV disease, and infants and children show dysfunctions, indicating the role of the impaired IFN response in severe disease in these groups [ 64 , 103 , 110 ].…”

Section: Respiratory Syncytial Virusmentioning

confidence: 99%

Interferons—Implications in the Immune Response to Respiratory Viruses

Bergeron,

Hansen,

Tripp

2023

Microorganisms

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Interferons (IFN) are an assemblage of signaling proteins made and released by various host cells in response to stimuli, including viruses. Respiratory syncytial virus (RSV), influenza virus, and SARS-CoV-2 are major causes of respiratory disease that induce or antagonize IFN responses depending on various factors. In this review, the role and function of type I, II, and III IFN responses to respiratory virus infections are considered. In addition, the role of the viral proteins in modifying anti-viral immunity is noted, as are the specific IFN responses that underly the correlates of immunity and protection from disease.

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Evaluation of nasal levels of interferon and clinical severity of influenza in children

Cited by 7 publications

References 68 publications

GBP5 Is an Interferon-Induced Inhibitor of Respiratory Syncytial Virus

GBP5 Is an Interferon-Induced Inhibitor of Respiratory Syncytial Virus

Role of Type I Interferon (IFN) in the Respiratory Syncytial Virus (RSV) Immune Response and Disease Severity

Interferons—Implications in the Immune Response to Respiratory Viruses

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