Lethal Synergism of 2009 Pandemic H1N1 Influenza Virus and Streptococcus pneumoniae Coinfection Is Associated with Loss of Murine Lung Repair Responses

ABSTRACTSecondary bacterial infections increase disease severity of influenza virus infections and contribute greatly to increased morbidity and mortality during pandemics. To study secondary bacterial infection following influenza virus infection, mice were inoculated with sublethal doses of 2009 seasonal H1N1 virus (NIH50) or pandemic H1N1 virus (Mex09) followed by inoculation withStreptococcus pneumoniae48 h later. Disease was characterized by assessment of weight loss and survival, titration of virus and bacteria by quantitative reverse transcription-PCR (qRT-PCR), histopathology, expression microarray, and immunohistochemistry. Mice inoculated with virus alone showed 100% survival for all groups. Mice inoculated with Mex09 plusS. pneumoniaeshowed severe weight loss and 100% mortality with severe alveolitis, denuded bronchiolar epithelium, and widespread expression of apoptosis marker cleaved caspase 3. In contrast, mice inoculated with NIH50 plusS. pneumoniaeshowed increased weight loss, 100% survival, and slightly enhanced lung pathology. Mex09-S. pneumoniaecoinfection also resulted in increasedS. pneumoniaereplication in lung and bacteremia late in infection. Global gene expression profiling revealed that Mex09-S. pneumoniaecoinfection did not induce significantly more severe inflammatory responses but featured significant loss of epithelial cell reproliferation and repair responses. Histopathological examination for cell proliferation marker MCM7 showed significant staining of airway epithelial cells in all groups except Mex09-S. pneumoniae-infected mice. This study demonstrates that secondary bacterial infection during 2009 H1N1 pandemic virus infection resulted in more severe disease and loss of lung repair responses than did seasonal influenza viral and bacterial coinfection. Moreover, this study provides novel insights into influenza virus and bacterial coinfection by showing correlation of lethal outcome with loss of airway basal epithelial cells and associated lung repair responses.IMPORTANCESecondary bacterial pneumonias lead to increased disease severity and have resulted in a significant percentage of deaths during influenza pandemics. To understand the biological basis for the interaction of bacterial and viral infections, mice were infected with sublethal doses of 2009 seasonal H1N1 and pandemic H1N1 viruses followed by infection withStreptococcus pneumoniae48 h later. Only infection with 2009 pandemic H1N1 virus andS. pneumoniaeresulted in severe disease with a 100% fatality rate. Analysis of the host response to infection during lethal coinfection showed a significant loss of responses associated with lung repair that was not observed in any of the other experimental groups. This group of mice also showed enhanced bacterial replication in the lung. This study reveals that the extent of lung damage during viral infection influences the severity of secondary bacterial infections and may help explain some differences in mortality during influenza pandemics.

Download Full-text

Neuraminidase Activity and Resistance of 2009 Pandemic H1N1 Influenza Virus to Antiviral Activity in Bronchoalveolar Fluid

Journal of Virology ◽

10.1128/jvi.00013-16 ◽

2016 ◽

Vol 90 (9) ◽

pp. 4637-4646 ◽

Cited By ~ 5

Author(s):

Kanyarat Ruangrung ◽

Ornpreya Suptawiwat ◽

Kittipong Maneechotesuwan ◽

Chompunuch Boonarkart ◽

Warunya Chakritbudsabong ◽

...

Keyword(s):

Influenza Virus ◽

Antiviral Activity ◽

H1n1 Virus ◽

H1n1 Influenza ◽

Surfactant Protein D ◽

Pandemic H1n1 ◽

Drug Resistant ◽

Bronchoalveolar Fluid ◽

Influenza Activity ◽

Resistant Strains

ABSTRACTHuman bronchoalveolar fluid is known to have anti-influenza activity. It is believed to be a frontline innate defense against the virus. Several antiviral factors, including surfactant protein D, are believed to contribute to the activity. The 2009 pandemic H1N1 influenza virus was previously shown to be less sensitive to surfactant protein D. Nevertheless, whether different influenza virus strains have different sensitivities to the overall anti-influenza activity of human bronchoalveolar fluid was not known. We compared the sensitivities of 2009 pandemic H1N1, seasonal H1N1, and seasonal H3N2 influenza virus strains to inhibition by human bronchoalveolar lavage (BAL) fluid. The pandemic and seasonal H1N1 strains showed lower sensitivity to human BAL fluid than the H3N2 strains. The BAL fluid anti-influenza activity could be enhanced by oseltamivir, indicating that the viral neuraminidase (NA) activity could provide resistance to the antiviral defense. In accordance with this finding, the BAL fluid anti-influenza activity was found to be sensitive to sialidase. The oseltamivir resistance mutation H275Y rendered the pandemic H1N1 virus but not the seasonal H1N1 virus more sensitive to BAL fluid. Since only the seasonal H1N1 but not the pandemic H1N1 had compensatory mutations that allowed oseltamivir-resistant strains to maintain NA enzymatic activity and transmission fitness, the resistance to BAL fluid of the drug-resistant seasonal H1N1 virus might play a role in viral fitness.IMPORTANCEHuman airway secretion contains anti-influenza activity. Different influenza strains may vary in their susceptibilities to this antiviral activity. Here we show that the 2009 pandemic and seasonal H1N1 influenza viruses were less sensitive to human bronchoalveolar lavage (BAL) fluid than H3N2 seasonal influenza virus. The resistance to the pulmonary innate antiviral activity of the pandemic virus was determined by its neuraminidase (NA) gene, and it was shown that the NA inhibitor resistance mutation H275Y abolished this resistance of the pandemic H1N1 but not the seasonal H1N1 virus, which had compensatory mutations that maintained the fitness of drug-resistant strains. Therefore, the innate respiratory tract defense may be a barrier against NA inhibitor-resistant mutants, and evasion of this defense may play a role in the emergence and spread of drug-resistant strains.

Download Full-text

Toxin-Antitoxin Genes of the Gram-Positive Pathogen Streptococcus pneumoniae: So Few and Yet So Many

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.00030-12 ◽

2012 ◽

Vol 76 (4) ◽

pp. 773-791 ◽

Cited By ~ 36

Author(s):

Wai Ting Chan ◽

Inma Moreno-Córdoba ◽

Chew Chieng Yeo ◽

Manuel Espinosa

Keyword(s):

Streptococcus Pneumoniae ◽

Biofilm Formation ◽

Bacterial Infections ◽

Host Cells ◽

Molecular Characteristics ◽

Type Ii ◽

Pneumococcal Infections ◽

Interesting Phenomenon ◽

Content Type ◽

Toxin Protein

SUMMARYPneumococcal infections cause up to 2 million deaths annually and raise a large economic burden and thus constitute an important threat to mankind. Because of the increase in the antibiotic resistance ofStreptococcus pneumoniaeclinical isolates, there is an urgent need to find new antimicrobial approaches to triumph over pneumococcal infections. Toxin-antitoxin (TA) systems (TAS), which are present in most living bacteria but not in eukaryotes, have been proposed as an effective strategy to combat bacterial infections. Type II TAS comprise a stable toxin and a labile antitoxin that form an innocuous TA complex under normal conditions. Under stress conditions, TA synthesis will be triggered, resulting in the degradation of the labile antitoxin and the release of the toxin protein, which would poison the host cells. The three functional chromosomal TAS fromS. pneumoniaethat have been studied as well as their molecular characteristics are discussed in detail in this review. Furthermore, a meticulous bioinformatics search has been performed for 48 pneumococcal genomes that are found in public databases, and more putative TAS, homologous to well-characterized ones, have been revealed. Strikingly, several unusual putative TAS, in terms of components and genetic organizations previously not envisaged, have been discovered and are further discussed. Previously, we reported a novel finding in which a unique pneumococcal DNA signature, the BOX element, affected the regulation of the pneumococcalyefM-yoeBTAS. This BOX element has also been found in some of the other pneumococcal TAS. In this review, we also discuss possible relationships between some of the pneumococcal TAS with pathogenicity, competence, biofilm formation, persistence, and an interesting phenomenon called bistability.

Download Full-text

Development, Characterization, and Standardization of a Nose-Only Inhalation Exposure System for Exposure of Rabbits to Small-Particle Aerosols ContainingFrancisella tularensis

Infection and Immunity ◽

10.1128/iai.00198-19 ◽

2019 ◽

Vol 87 (8) ◽

Cited By ~ 4

Author(s):

Katherine J. O’Malley ◽

Jennifer D. Bowling ◽

Eileen M. Barry ◽

Karsten R. O. Hazlett ◽

Douglas S. Reed

Keyword(s):

Weight Loss ◽

Median Survival ◽

Bacterial Culture ◽

Severe Disease ◽

Inhalation Exposure ◽

Brain Heart Infusion ◽

Survival Times ◽

Exposure System ◽

Content Type ◽

Schu S4

ABSTRACTInhalation ofFrancisella tularensiscauses pneumonic tularemia in humans, a severe disease with a 30 to 60% mortality rate. The reproducible delivery of aerosolized virulent bacteria in relevant animal models is essential for evaluating medical countermeasures. Here we developed optimized protocols for infecting New Zealand White (NZW) rabbits with aerosols containingF. tularensis. We evaluated the relative humidity, aerosol exposure technique, and bacterial culture conditions to optimize the spray factor (SF), a central metric of aerosolization. This optimization reduced both inter- and intraday variability and was applicable to multiple isolates ofF. tularensis. Further improvements in the accuracy and precision of the inhaled pathogen dose were achieved through enhanced correlation of the bacterial culture optical density and the number of CFU. Plethysmograph data collected during exposures found that respiratory function varied considerably between rabbits, was not a function of weight, and did not improve with acclimation to the system. Live vaccine strain (LVS)-vaccinated rabbits were challenged via aerosol with human-virulentF. tularensisSCHU S4 that had been cultivated in either Mueller-Hinton broth (MHB) or brain heart infusion (BHI) broth. LVS-vaccinated animals challenged with SCHU S4 that had been cultivated in MHB experienced short febrile periods (median, 3.2 days), limited weight loss (<5%), and longer median survival times (∼18 days) that were significantly different from those for unvaccinated controls. In contrast, LVS-vaccinated rabbits challenged with SCHU S4 that had been cultivated in BHI experienced longer febrile periods (median, 5.5 days) and greater weight loss (>10%) than the unvaccinated controls and median survival times that were not significantly different from those for the unvaccinated controls. These studies highlight the importance of careful characterization and optimization of protocols for aerosol challenge with pathogenic agents.

Download Full-text

Allergic Airway Disease Prevents Lethal Synergy of Influenza A Virus-Streptococcus pneumoniaeCoinfection

mBio ◽

10.1128/mbio.01335-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 4

Author(s):

Sean Roberts ◽

Sharon L. Salmon ◽

Donald J. Steiner ◽

Clare M. Williams ◽

Dennis W. Metzger ◽

...

Keyword(s):

Influenza Virus ◽

Streptococcus Pneumoniae ◽

Influenza Infection ◽

Airway Disease ◽

Allergic Airway Disease ◽

Bacterial Clearance ◽

Content Type ◽

Ifn Γ ◽

The Impact ◽

First Time

ABSTRACTFatal outcomes following influenza infection are often associated with secondary bacterial infections. Allergic airway disease (AAD) is known to influence severe complications from respiratory infections, and yet the mechanistic effect of AAD on influenza virus-Streptococcus pneumoniaecoinfection has not been investigated previously. We examined the impact of AAD on host susceptibility to viral-bacterial coinfections. We report that AAD improved survival during coinfection when viral-bacterial challenge occurred 1 week after AAD. Counterintuitively, mice with AAD had significantly deceased proinflammatory responses during infection. Specifically, both CD4+and CD8+T cell interferon gamma (IFN-γ) responses were suppressed following AAD. Resistance to coinfection was also associated with strong transforming growth factor β1 (TGF-β1) expression and increased bacterial clearance. Treatment of AAD mice with IFN-γ or genetic deletion of TGF-β receptor II expression reversed the protective effects of AAD. Using a novel triple-challenge model system, we show for the first time that AAD can provide protection against influenza virus-S. pneumoniaecoinfection through the production of TGF-β that suppresses the influenza virus-induced IFN-γ response, thereby preserving antibacterial immunity.IMPORTANCEAsthma has become one of the most common chronic diseases and has been identified as a risk factor for developing influenza. However, the impact of asthma on postinfluenza secondary bacterial infection is currently not known. Here, we developed a novel triple-challenge model of allergic airway disease, primary influenza infection, and secondaryStreptococcus pneumoniaeinfection to investigate the impact of asthma on susceptibility to viral-bacterial coinfections. We report for the first time that mice recovering from acute allergic airway disease are highly resistant to influenza-pneumococcal coinfection and that this resistance is due to inhibition of influenza virus-mediated impairment of bacterial clearance. Further characterization of allergic airway disease-associated resistance against postinfluenza secondary bacterial infection may aid in the development of prophylactic and/or therapeutic treatment against coinfection.

Download Full-text

Swine Influenza Virus PA and Neuraminidase Gene Reassortment into Human H1N1 Influenza Virus Is Associated with an Altered Pathogenic Phenotype Linked to Increased MIP-2 Expression

Journal of Virology ◽

10.1128/jvi.00087-15 ◽

2015 ◽

Vol 89 (10) ◽

pp. 5651-5667 ◽

Cited By ~ 6

Author(s):

Daniel Dlugolenski ◽

Les Jones ◽

Elizabeth Howerth ◽

David Wentworth ◽

S. Mark Tompkins ◽

...

Keyword(s):

Influenza Virus ◽

Sialic Acid ◽

Influenza A ◽

H1n1 Virus ◽

Swine Influenza ◽

Influenza Viruses ◽

Pandemic H1n1 ◽

Human Influenza ◽

Swine Virus ◽

Virus Reassortment

ABSTRACTSwine are susceptible to infection by both avian and human influenza viruses, and this feature is thought to contribute to novel reassortant influenza viruses. In this study, the influenza virus reassortment rate in swine and human cells was determined. Coinfection of swine cells with 2009 pandemic H1N1 virus (huH1N1) and an endemic swine H1N2 (A/swine/Illinois/02860/09) virus (swH1N2) resulted in a 23% reassortment rate that was independent of α2,3- or α2,6-sialic acid distribution on the cells. The reassortants had altered pathogenic phenotypes linked to introduction of the swine virus PA and neuraminidase (NA) into huH1N1. In mice, the huH1N1 PA and NA mediated increased MIP-2 expression early postinfection, resulting in substantial pulmonary neutrophilia with enhanced lung pathology and disease. The findings support the notion that swine are a mixing vessel for influenza virus reassortants independent of sialic acid distribution. These results show the potential for continued reassortment of the 2009 pandemic H1N1 virus with endemic swine viruses and for reassortants to have increased pathogenicity linked to the swine virus NA and PA genes which are associated with increased pulmonary neutrophil trafficking that is related to MIP-2 expression.IMPORTANCEInfluenza A viruses can change rapidly via reassortment to create a novel virus, and reassortment can result in possible pandemics. Reassortments among subtypes from avian and human viruses led to the 1957 (H2N2 subtype) and 1968 (H3N2 subtype) human influenza pandemics. Recent analyses of circulating isolates have shown that multiple genes can be recombined from human, avian, and swine influenza viruses, leading to triple reassortants. Understanding the factors that can affect influenza A virus reassortment is needed for the establishment of disease intervention strategies that may reduce or preclude pandemics. The findings from this study show that swine cells provide a mixing vessel for influenza virus reassortment independent of differential sialic acid distribution. The findings also establish that circulating neuraminidase (NA) and PA genes could alter the pathogenic phenotype of the pandemic H1N1 virus, resulting in enhanced disease. The identification of such factors provides a framework for pandemic modeling and surveillance.

Download Full-text

A North American H7N3 Influenza Virus Supports Reassortment with 2009 Pandemic H1N1 and Induces Disease in Mice without Prior Adaptation

Journal of Virology ◽

10.1128/jvi.02761-15 ◽

2016 ◽

Vol 90 (9) ◽

pp. 4796-4806 ◽

Cited By ~ 7

Author(s):

Graham D. Williams ◽

Amelia K. Pinto ◽

Brittany Doll ◽

Adrianus C. M. Boon

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

North American ◽

H1n1 Virus ◽

Influenza Viruses ◽

Pandemic H1n1 ◽

Reassortant Viruses ◽

H7n3 Virus ◽

Prior Adaptation

ABSTRACTReassortment between H5 or H9 subtype avian and mammalian influenza A viruses (IAV) can generate a novel virus that causes disease and transmits between mammals. Such information is currently not available for H7 subtype viruses. We evaluated the ability of a low-pathogenicity North American avian H7N3 virus (A/shorebird/Delaware/22/2006) to reassort with mammalian or avian viruses using a plasmid-based competition assay. In addition to genome segments derived from an avian H7N9 virus, the H7N3 virus reassorted efficiently with the PB2, NA, and M segments from the 2009 pandemic H1N1 (PH1N1) virus.In vitroandin vivoevaluation of the H7N3:PH1N1 (7 + 1) reassortant viruses revealed that the PB2, NA, or M segments fromPH1N1 largely do not attenuate the H7N3 virus, whereas the PB1, PA, NP, or NS genome segments fromPH1N1 do. Additionally, we assessed the functionality of the H7N3:PH1N1 7 + 1 reassortant viruses by measuring the inflammatory responsein vivo. We found that infection with wild-type H7N3 resulted in increased inflammatory cytokine production relative to that seen with thePH1N1 strain and that the increase was further exacerbated by substitution ofPH1N1 PB2 but not NA or M. Finally, we assessed if any adaptations occurred in the individually substituted segments afterin vivoinoculation and found no mutations, suggesting thatPH1N1 PB2, NA, and M are genetically stable in the background of this H7N3 virus. Taking the data together, we demonstrate that a North American avian H7N3 IAV is genetically and functionally compatible with multiple gene segments from the 2009 pandemic influenza virus strain without prior adaptation.IMPORTANCEThe 2009 pandemic H1N1 virus continues to circulate and reassort with other influenza viruses, creating novel viruses with increased replication and transmission potential in humans. Previous studies have found that this virus can also reassort with H5N1 and H9N2 avian influenza viruses. We now show that several genome segments of the 2009 H1N1 virus are also highly compatible with a low-pathogenicity avian H7N3 virus and that these reassortant viruses are stable and not attenuated in an animal model. These results highlight the potential for reassortment of H1N1 viruses with avian influenza virus and emphasize the need for continued surveillance of influenza viruses in areas of cocirculation between avian, human, and swine viruses.

Download Full-text

High Incidence of Severe Influenza among Individuals over 50 Years of Age

Clinical and Vaccine Immunology ◽

10.1128/cvi.05357-11 ◽

2011 ◽

Vol 18 (11) ◽

pp. 1918-1924 ◽

Cited By ~ 21

Author(s):

Anna J. X. Zhang ◽

Kelvin K. W. To ◽

Herman Tse ◽

Kwok-Hung Chan ◽

Kun-Yuan Guo ◽

...

Keyword(s):

Influenza Vaccination ◽

Incidence Rate ◽

Old Age ◽

H1n1 Virus ◽

Severe Disease ◽

Age Groups ◽

Respiratory Viruses ◽

World Health ◽

Pandemic H1n1 ◽

Age Group

ABSTRACTAge-specific epidemiological data on asymptomatic, symptomatic, and severe infections are essential for public health policies on combating influenza. In this study, we incorporated data on microbiologically confirmed infections and seroprevalence to comprehensively describe the epidemiology of pandemic H1N1 2009 influenza. Seroprevalence was determined from 1,795 random serum samples collected in our hospital in January 2007 (before the first wave of the pandemic) and March 2010 (after the second wave). Data on microbiologically confirmed infection and severe cases were obtained from the Centre for Health Protection in Hong Kong. Severe cases were most common in the 51- to 60-year-old age group. The microbiologically confirmed incidence rate was highest for children aged ≤10 years and dropped sharply for the adult population (ρ = −1.0;P< 0.01), but the incidence rate for severe disease was highest for the 51- to 60-year-old age group. For the 51- to 60-year-old age group, the seroprevalence was similar to that for the younger age groups, but the proportion of severe cases relative to seroprevalence was significantly higher than that for 11- to 50-year-old age groups. As judged from the percentage of specimens positive for other respiratory viruses compared with that for pandemic H1N1 virus, the impact of symptomatic disease due to pandemic H1N1 virus was higher than that for other respiratory viruses in people aged ≤50 years. In conclusion, the 51- to 60-year-old age group, which had the highest overall incidence and the highest rate of severe disease but is currently not considered by the World Health Organization to be an at-risk group, should be prioritized for influenza vaccination in areas where universal influenza vaccination is not practiced.

Download Full-text

Recombinant H1N1 virus-like particle vaccine elicits protective immunity in ferrets against the 2009 pandemic H1N1 influenza virus

Vaccine ◽

10.1016/j.vaccine.2010.04.093 ◽

2010 ◽

Vol 28 (30) ◽

pp. 4771-4776 ◽

Cited By ~ 52

Author(s):

Peter Pushko ◽

Thomas Kort ◽

Margret Nathan ◽

Melissa B. Pearce ◽

Gale Smith ◽

...

Keyword(s):

Influenza Virus ◽

Protective Immunity ◽

H1n1 Virus ◽

H1n1 Influenza ◽

Pandemic H1n1 ◽

H1n1 Influenza Virus ◽

Pandemic H1n1 Influenza ◽

Virus Like Particle

Download Full-text

Cigarette Smoke Attenuates the Nasal Host Response to Streptococcus pneumoniae and Predisposes to Invasive Pneumococcal Disease in Mice

Infection and Immunity ◽

10.1128/iai.01504-15 ◽

2016 ◽

Vol 84 (5) ◽

pp. 1536-1547 ◽

Cited By ~ 14

Author(s):

Pamela Shen ◽

Mathieu C. Morissette ◽

Gilles Vanderstocken ◽

Yang Gao ◽

Muhammad Hassan ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Cigarette Smoke ◽

Invasive Pneumococcal Disease ◽

Bacterial Infections ◽

Pneumococcal Disease ◽

Pneumococcal Infection ◽

Cigarette Smoke Exposure ◽

Upper Respiratory Tract ◽

Content Type ◽

Pneumococcal Colonization

Streptococcus pneumoniaeis a leading cause of invasive bacterial infections, with nasal colonization an important first step in disease. While cigarette smoking is a strong risk factor for invasive pneumococcal disease, the underlying mechanisms remain unknown. This is partly due to a lack of clinically relevant animal models investigating nasal pneumococcal colonization in the context of cigarette smoke exposure. We present a model of nasal pneumococcal colonization in cigarette smoke-exposed mice and document, for the first time, that cigarette smoke predisposes to invasive pneumococcal infection and mortality in an animal model. Cigarette smoke increased the risk of bacteremia and meningitis without prior lung infection. Mechanistically, deficiency in interleukin 1α (IL-1α) or platelet-activating factor receptor (PAFR), an important host receptor thought to bind and facilitate pneumococcal invasiveness, did not rescue cigarette smoke-exposed mice from invasive pneumococcal disease. Importantly, we observed cigarette smoke to attenuate nasal inflammatory mediator expression, particularly that of neutrophil-recruiting chemokines, normally elicited by pneumococcal colonization. Smoking cessation during nasal pneumococcal colonization rescued nasal neutrophil recruitment and prevented invasive disease in mice. We propose that cigarette smoke predisposes to invasive pneumococcal disease by suppressing inflammatory processes of the upper respiratory tract. Given that smoking prevalence remains high worldwide, these findings are relevant to the continued efforts to reduce the invasive pneumococcal disease burden.

Download Full-text

Toll-Like Receptor 4 Agonistic Antibody Promotes Innate Immunity against Severe Pneumonia Induced by Coinfection with Influenza Virus and Streptococcus pneumoniae

Clinical and Vaccine Immunology ◽

10.1128/cvi.00010-13 ◽

2013 ◽

Vol 20 (7) ◽

pp. 977-985 ◽

Cited By ~ 19

Author(s):

Akitaka Tanaka ◽

Shigeki Nakamura ◽

Masafumi Seki ◽

Kenji Fukudome ◽

Naoki Iwanaga ◽

...

Keyword(s):

Innate Immunity ◽

Influenza Virus ◽

Streptococcus Pneumoniae ◽

Pneumococcal Pneumonia ◽

Survival Rates ◽

Severe Pneumonia ◽

Histopathological Study ◽

Toll Like Receptor ◽

Content Type ◽

Monocyte Chemoattractant Protein 1

ABSTRACTCoinfection with bacteria is a major cause of mortality during influenza epidemics. Recently, Toll-like receptor (TLR) agonists were shown to have immunomodulatory functions. In the present study, we investigated the effectiveness and mechanisms of the new TLR4 agonistic monoclonal antibody UT12 against secondary pneumococcal pneumonia induced by coinfection with influenza virus in a mouse model. Mice were intranasally inoculated withStreptococcus pneumoniae2 days after influenza virus inoculation. UT12 was intraperitoneally administered 2 h before each inoculation. Survival rates were significantly increased and body weight loss was significantly decreased by UT12 administration. Additionally, the production of inflammatory mediators was significantly suppressed by the administration of UT12. In a histopathological study, pneumonia in UT12-treated mice was very mild compared to that in control mice. UT12 increased antimicrobial defense through the acceleration of macrophage recruitment into the lower respiratory tract induced by c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NF-κB) pathway-dependent monocyte chemoattractant protein 1 (MCP-1) production. Collectively, these findings indicate that UT12 promoted pulmonary innate immunity and may reduce the severity of severe pneumonia induced by coinfection with influenza virus andS. pneumoniae. This immunomodulatory effect of UT12 improves the prognosis of secondary pneumococcal pneumonia and makes UT12 an attractive candidate for treating severe infectious diseases.

Download Full-text