Intranasal Administration of the TLR2 Agonist Pam2Cys Provides Rapid Protection against Influenza in Mice

Tan, Andrew M.; Mifsud, Edin; Zeng, Weiguang; Edenborough, Kathryn M.; McVernon, Jodie; Brown, Lorena E.; Jackson, David C.

doi:10.1021/mp300257x

Cited by 106 publications

(138 citation statements)

References 42 publications

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“…Specifically, while the innate immune response to B. pertussis is primarily TLR-4-mediated [16], the responses to both M. pneumoniae [17, 18] and C. pneumoniae [19] are driven in large part by TLR-2-mediated pathways. This distinction is important in the context of our analysis, as proper clearance of influenza is also known to rely heavily on TLR-2 recognition [20, 21]. These commonalities in the innate immune recognition of influenza virus and M. and C. pneumoniae could abrogate coinfections with these pathogens and explain the antagonistic effects described here.…”

Section: Discussionmentioning

confidence: 99%

Estimating the prevalence of coinfection with influenza virus and the atypical bacteria Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae

Mina

Burke

Klugman

2014

Eur J Clin Microbiol Infect Dis

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Coinfections with common bacterial respiratory pathogens and influenza viruses are well-known causes of disease, often via synergistic interactions between the influenza virus, the bacteria, and the human host. However, relatively little is known about interactions between atypical bacteria and influenza viruses. A recent report by Reinton et al. explored this issue by analyzing data from 3,661 patients seeking medical assistance for the presence of Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Bordetella pertussis, as well as influenza A or B virus in nasal swab specimens. The report, however, did not accurately assess the epidemiologic interactions of these pathogens. We aimed to describe the interactions between these bacterial species and influenza infections. Strong and highly statistically significant antagonistic interspecies interactions were detected between C. pneumoniae and influenza virus [odds ratio (OR): 0.09; p<0.0001) and M. pneumoniae and influenza virus infections (OR: 0.29; p=0.003). No association was detected between B. pertussis and influenza infection (p=0.34), contrary to the initial report, and coinfection was not detected at a higher-than-by-chance frequency within the population. Further support of these results is supplied by the analysis of two earlier investigations reporting data on influenza virus and these atypical bacteria. Our results supplement the large body of literature regarding interactions between influenza virus and typical respiratory pathogens, providing a fuller picture of the spectrum of interactions between influenza viruses and respiratory bacteria. Further, we demonstrate the importance of choosing the most appropriate reference populations for the analysis being performed and describe the pitfalls that may occur when care is not taken in this regard.

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Section: Discussionmentioning

confidence: 99%

Estimating the prevalence of coinfection with influenza virus and the atypical bacteria Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae

Mina

Burke

Klugman

2014

Eur J Clin Microbiol Infect Dis

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“…It is quite possible that steroid treatment could be effective in humans, but the timing and magnitude of the drug has not yet been optimized. Tan et al [47] have shown Pam2Cys, a TLR-2 agonist, can instigate an inflammatory response even in the absence of an antigen. Mice pre-treated with Pam2Cys were protected from the H1N1 virus for up to seven days post-treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of these compounds on the dynamic response of the lung immune systems has not been determined. Several experiments have indicated a protective effect of pre-stimulation of TLR pathways before influenza infection in murine models [46][47][48][49]. We tested the three ODE models to determine whether they could replicate these experimental results.…”

Section: Models' Response To Simulated Ifn Pre-stimulationmentioning

confidence: 91%

A Systems and Treatment Perspective of Models of Influenza Virus-Induced Host Responses

2018

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Abstract:Severe influenza infections are often characterized as having unique host responses (e.g., early, severe hypercytokinemia). Neuraminidase inhibitors can be effective in controlling the severe symptoms of influenza but are often not administered until late in the infection. Several studies suggest that immune modulation may offer protection to high risk groups. Here, we review the current state of mathematical models of influenza-induced host responses. Selecting three models with conserved immune response components, we determine if the immune system components which most affect virus replication when perturbed are conserved across the models. We also test each model's response to a pre-induction of interferon before the virus is administered. We find that each model emphasizes the importance of controlling the infected cell population to control viral replication. Moreover, our work shows that the structure of current models does not allow for significant responses to increased interferon concentrations. These results suggest that the current library of available published models of influenza infection does not adequately represent the complex interactions of the virus, interferon, and other aspects of the immune response. Specifically, the method used to model virus-resistant cells may need to be adapted in future work to more realistically represent the immune response to viral infection.

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“…Specific TLR-mediated immunostimulation was also demonstrated in previous studies to increase the innate immune response and resistance to lethal influenza virus monoinfection in vivo. However, treatment was initiated prior to infection (42,43) or no later than 24 h after infection (44), although a highly increased susceptibility to secondary pneumococcal invasion associated with impaired bacterial clearance (19) and high mortality rates (45) was detected between days 5 and 7 after influenza virus infection. Notably, in the present study, pulmonary TLR-mediated immunostimulation with MALP-2 effectively increased the level of proinflammatory IL-1␤ and subsequent immigration of leukocytes, particularly neutrophils and macrophages, into murine airways even 6 days after IAV infection, despite an ongoing antiviral host defense.…”

Section: Discussionmentioning

confidence: 99%

“…In the current study, pulmonary immune stimulation with MALP-2 5 days after IAV infection (24 h before pneumococcal challenge) also resulted in decreased lung bacterial loads 24 h after bacterial infection. Moreover, specific TLR-mediated immunostimulation prior to or shortly after experimental influenza virus monoinfection has been shown to reduce the viral titer (43,44). However, MALP-2 treatment performed on day 5 after IAV infection had no effect on viral load or viral distribution in the murine lung tissue.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Immunostimulation with MALP-2 in Influenza Virus-Infected Mice Increases Survival after Pneumococcal Superinfection

et al. 2015

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e Pulmonary infection with influenza virus is frequently complicated by bacterial superinfection, with Streptococcus pneumoniae being the most prevalent causal pathogen and hence often associated with high morbidity and mortality rates. Local immunosuppression due to pulmonary influenza virus infection has been identified as a major cause of the pathogenesis of secondary bacterial lung infection. Thus, specific local stimulation of the pulmonary innate immune system in subjects with influenza virus infection might improve the host defense against secondary bacterial pathogens. In the present study, we examined the effect of pulmonary immunostimulation with Toll-like receptor 2 (TLR-2)-stimulating macrophage-activating lipopeptide 2 (MALP-2) in influenza A virus (IAV)-infected mice on the course of subsequent pneumococcal superinfection. Female C57BL/6N mice infected with IAV were treated with MALP-2 on day 5 and challenged with S. pneumoniae on day 6. Intratracheal MALP-2 application increased proinflammatory cytokine and chemokine release and enhanced the recruitment of leukocytes, mainly neutrophils, into the alveolar space of IAV-infected mice, without detectable systemic side effects. Local pulmonary instillation of MALP-2 in IAV-infected mice 24 h before transnasal pneumococcal infection considerably reduced the bacterial number in the lung tissue without inducing exaggerated inflammation. The pulmonary viral load was not altered by MALP-2. Clinically, MALP-2 treatment of IAV-infected mice increased survival rates and reduced hypothermia and body weight loss after pneumococcal superinfection compared to those of untreated coinfected mice. In conclusion, local immunostimulation with MALP-2 in influenza virus-infected mice improved pulmonary bacterial elimination and increased survival after subsequent pneumococcal superinfection. P neumonia is a significant cause of morbidity and the fourth leading cause of death worldwide (http://www.who.int/ mediacentre/factsheets/fs310/en/), with Streptococcus pneumoniae being the most prevalent causative agent identified in lower respiratory tract infections (1, 2). The risk of pneumonia is greatly enhanced in specific pathological situations with an impaired pulmonary host defense, including long-term ventilation (3), strokeinduced immune depression (4, 5), sepsis-associated immune paralysis (6), and viral lung infections (7). In particular, pulmonary infections with seasonal circulating (8) or pandemic (9) influenza viruses are frequently complicated by bacterial superinfection, resulting in a severe pneumonia often associated with high mortality rates. S. pneumoniae is one of the most common bacterial pathogens of severe postinfluenza bacterial pneumonia (8).Influenza viruses have been reported to impair the pulmonary host defense against bacteria via different mechanisms, thus promoting secondary bacterial infections. Bacterial adherence was shown to be facilitated by influenza virus-induced cytolysis and apoptosis (10, 11) and by upregulation of platelet-activating ...

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Intranasal Administration of the TLR2 Agonist Pam2Cys Provides Rapid Protection against Influenza in Mice

Cited by 106 publications

References 42 publications

Estimating the prevalence of coinfection with influenza virus and the atypical bacteria Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae

Estimating the prevalence of coinfection with influenza virus and the atypical bacteria Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae

A Systems and Treatment Perspective of Models of Influenza Virus-Induced Host Responses

Pulmonary Immunostimulation with MALP-2 in Influenza Virus-Infected Mice Increases Survival after Pneumococcal Superinfection

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