Host Physiologic Changes Induced by Influenza A Virus Lead toStaphylococcus aureusBiofilm Dispersion and Transition from Asymptomatic Colonization to Invasive Disease

ABSTRACTStaphylococcus aureusis a ubiquitous opportunistic human pathogen and a major health concern worldwide, causing a wide variety of diseases from mild skin infections to systemic disease.S. aureusis a major source of severe secondary bacterial pneumonia after influenza A virus infection, which causes widespread morbidity and mortality. While the phenomenon of secondary bacterial pneumonia is well established, the mechanisms behind the transition from asymptomatic colonization to invasive staphylococcal disease following viral infection remains unknown. In this report, we have shown thatS. aureusbiofilms, grown on an upper respiratory epithelial substratum, disperse in response to host physiologic changes related to viral infection, such as febrile range temperatures, exogenous ATP, norepinephrine, and increased glucose. Mice that were colonized withS. aureusand subsequently exposed to these physiologic stimuli or influenza A virus coinfection developed pronounced pneumonia. This study provides novel insight into the transition from colonization to invasive disease, providing a better understanding of the events involved in the pathogenesis of secondary staphylococcal pneumonia.IMPORTANCEIn this study, we have determined that host physiologic changes related to influenza A virus infection causesS. aureusto disperse from a biofilm state. Additionally, we report that these same host physiologic changes promoteS. aureusdissemination from the nasal tissue to the lungs in an animal model. Furthermore, this study identifies important aspects involved in the transition ofS. aureusfrom asymptomatic colonization to pneumonia.

Download Full-text

GP96 Drives Exacerbation of Secondary Bacterial Pneumonia following Influenza A Virus Infection

mBio ◽

10.1128/mbio.03269-20 ◽

2021 ◽

Author(s):

Tomoko Sumitomo ◽

Masanobu Nakata ◽

Satoshi Nagase ◽

Yuki Takahara ◽

Mariko Honda-Ogawa ◽

...

Keyword(s):

Virus Infection ◽

Bacterial Infection ◽

Influenza A Virus ◽

Bacterial Pneumonia ◽

Influenza A ◽

Early Stage ◽

Pathogenic Mechanism ◽

Influenza A Virus Infection ◽

Secondary Bacterial Pneumonia ◽

Increased Susceptibility

Secondary bacterial pneumonia following an influenza A virus (IAV) infection is a major cause of morbidity and mortality. Although it is generally accepted that preceding IAV infection leads to increased susceptibility to secondary bacterial infection, details regarding the pathogenic mechanism during the early stage of superinfection remain elusive.

Download Full-text

Immune Response Induced by Airway Sensitization after Influenza A Virus Infection Depends on Timing of Antigen Exposure in Mice

Journal of Virology ◽

10.1128/jvi.75.1.499-505.2001 ◽

2001 ◽

Vol 75 (1) ◽

pp. 499-505 ◽

Cited By ~ 20

Author(s):

Naomi Yamamoto ◽

Shunsuke Suzuki ◽

Yuzo Suzuki ◽

Akira Shirai ◽

Masatoshi Nakazawa ◽

...

Keyword(s):

Immune Response ◽

Virus Infection ◽

Lymph Nodes ◽

Viral Infection ◽

Influenza A Virus ◽

Acute Phase ◽

Influenza A ◽

Recovery Phase ◽

Phase Group ◽

Influenza A Virus Infection

ABSTRACT To study which phase of viral infection promotes antigen sensitization via the airway and which type of antigen-presenting cells contributes to antigen sensitization, BALB/c mice were sensitized by inhalation of ovalbumin (OA) during the acute phase or the recovery phase of influenza A virus infection, and then 3 weeks later animals were challenged with OA. The numbers of eosinophils and lymphocytes, the amounts of interleukin-4 (IL-4) and IL-5 in the bronchoalveolar lavage fluid, and the serum levels of OA-specific immunoglobulin G1 (IgG1) and IgE increased in mice sensitized during the acute phase (acute phase group), while a high level of gamma interferon production was detected in those sensitized during the recovery phase (recovery phase group). In the acute phase group, both major histocompatibility complex class II molecules and CD11c were strongly stained on the bronchial epithelium; in the recovery phase group, however, neither molecule was detected. OA-capturing dendritic cells (DCs) migrated to the regional lymph nodes, and a small number of OA-capturing macrophages were also observed in the lymph nodes of the acute phase group. In the recovery group, however, no OA-capturing DCs were detected in either the lungs or the lymph nodes, while OA-capturing macrophages were observed in the lymph nodes. These results indicate that the timing of antigen sensitization after viral infection determines the type of immune response.

Download Full-text

Lambda Interferon Is the Predominant Interferon Induced by Influenza A Virus Infection In Vivo

Journal of Virology ◽

10.1128/jvi.01703-09 ◽

2010 ◽

Vol 84 (21) ◽

pp. 11515-11522 ◽

Cited By ~ 165

Author(s):

Nancy A. Jewell ◽

Troy Cline ◽

Sara E. Mertz ◽

Sergey V. Smirnov ◽

Emilio Flaño ◽

...

Keyword(s):

Virus Infection ◽

Influenza A Virus ◽

Influenza A ◽

Systemic Disease ◽

Receptor Expression ◽

Type I ◽

Type I Ifn ◽

Type Iii ◽

Influenza A Virus Infection ◽

Type Iii Ifn

ABSTRACTThe type I alpha/beta interferons (IFN-α/β) are known to play an important role in host defense against influenza A virus infection, but we have now discovered that the recently identified type III IFNs (IFN-λ) constitute the major response to intranasal infection with this virus. Type III IFNs were present at much higher levels than type I IFNs in the lungs of infected mice, and the enhanced susceptibility of STAT2−/−animals demonstrated that only signaling through the IFN-α/β or IFN-λ pathways was sufficient to mediate protection. This finding offers a possible explanation for the similar levels of antiviral protection found in wild-type (WT) mice and in animals lacking a functional type I IFN receptor (IFNAR−/−) but also argues that our current understanding of type III IFN induction is incomplete. While murine IFN-λ production is thought to depend on signaling through the type I IFN receptor, we demonstrate that intranasal influenza A virus infection leads to the robust type III IFN induction in the lungs of both WT and IFNAR−/−mice. This is consistent with previous studies showing that IFNAR-mediated protection is redundant for mucosal influenza virus infection and with data showing that the type III IFN receptor is expressed primarily by epithelial cells. However, the overlapping effects of these two cytokine families are limited by their differential receptor expression, with a requirement for IFN-α/β signaling in combating systemic disease.

Download Full-text

Modeling Surface Disinfection Needs To Meet Microbial Risk Reduction Targets

Applied and Environmental Microbiology ◽

10.1128/aem.00709-18 ◽

2018 ◽

Vol 84 (18) ◽

Cited By ~ 9

Author(s):

Amanda M. Wilson ◽

Kelly A. Reynolds ◽

Jonathan D. Sexton ◽

Robert A. Canales

Keyword(s):

Health Care ◽

Virus Infection ◽

Viral Infection ◽

Influenza A Virus ◽

Influenza A ◽

Surface Concentration ◽

Infection Risk ◽

Surface Cleaning ◽

Surface Disinfection ◽

Influenza A Virus Infection

ABSTRACTNosocomial viral infections are an important cause of health care-acquired infections where fomites have a role in transmission. Using stochastic modeling to quantify the effects of surface disinfection practices on nosocomial pathogen exposures and infection risk can inform cleaning practices. The purpose of this study was to predict the effect of surface disinfection on viral infection risks and to determine needed viral reductions to achieve risk targets. Rotavirus, rhinovirus, and influenza A virus infection risks for two cases were modeled. Case 1 utilized a single fomite contact approach, while case 2 assumed 6 h of contact activities. A 94.1% viral reduction on surfaces and hands was measured following a single cleaning round using an Environmental Protection Agency (EPA)-registered disinfectant in an urgent care facility. This value was used to model the effect of a surface disinfection intervention on infection risk. Risk reductions for other surface-cleaning efficacies were also simulated. Surface reductions required to achieve risk probability targets were estimated. Under case 1 conditions, a 94.1% reduction in virus surface concentration reduced infection risks by 94.1%. Under case 2 conditions, a 94.1% reduction on surfaces resulted in median viral infection risks being reduced by 92.96 to 94.1% and an influenza A virus infection risk below one in a million. Surface concentration in the equations was highly correlated with dose and infection risk outputs. For rotavirus and rhinovirus, a >99.99% viral surface reduction would be needed to achieve a one-in-a-million risk target. This study quantifies reductions of infection risk relative to surface disinfectant use and demonstrates that risk targets for low-infectious-dose organisms may be more challenging to achieve.IMPORTANCEIt is known that the use of EPA-registered surface disinfectant sprays can reduce infection risk if used according to the manufacturer's instructions. However, there are currently no standards for health care environments related to contamination levels on surfaces. The significance of this research is in quantifying needed reductions to meet various risk targets using realistic viral concentrations on surfaces for health care environments. This research informs the design of cleaning protocols by demonstrating that multiple applications may be needed to reduce risk and by highlighting a need for more models exploring the relationship among microbial contamination of surfaces, patient and health care worker behaviors, and infection risks.

Download Full-text

Targeting Organic Anion Transporter 3 with Probenecid as a Novel Anti-Influenza A Virus Strategy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01532-12 ◽

2012 ◽

Vol 57 (1) ◽

pp. 475-483 ◽

Cited By ~ 26

Author(s):

Olivia Perwitasari ◽

Xiuzhen Yan ◽

Scott Johnson ◽

Caleb White ◽

Paula Brooks ◽

...

Keyword(s):

Virus Infection ◽

Influenza A Virus ◽

Virus Replication ◽

Influenza A ◽

Organic Anion ◽

Organic Anion Transporter ◽

Health Concern ◽

Anion Transporter ◽

Influenza A Virus Infection ◽

Organic Anion Transporter 3

ABSTRACTInfluenza A virus infection is a major global health concern causing significant mortality, morbidity, and economic loss. Antiviral chemotherapeutics that target influenza A virus are available; however, rapid emergence of drug-resistant strains has been reported. Consequently, there is a burgeoning need to identify novel anti-influenza A drugs, particularly those that target host gene products required for virus replication, to reduce the likelihood of drug resistance. In this study, a small interfering RNA (siRNA) screen was performed to identify host druggable gene targets for anti-influenza A virus therapy. The host organic anion transporter-3 gene (OAT3), a member of the SLC22 family of transporters, was validated as being required to support influenza A virus replication. Probenecid, a prototypical uricosuric agent and chemical inhibitor of organic anion transporters known to target OAT3, was shown to be effective in limiting influenza A virus infectionin vitro(50% inhibitory concentration [IC50] of 5.0 × 10−5to 5.0 × 10−4μM;P< 0.005) andin vivo(P< 0.05). Probenecid is widely used for treatment of gout and related hyperuricemic disorders, has been extensively studied for pharmacokinetics and safety, and represents an excellent candidate for drug repositioning as a novel anti-influenza A chemotherapeutic.

Download Full-text

Streptococcus pneumoniae Modulates Staphylococcus aureus Biofilm Dispersion and the Transition from Colonization to Invasive Disease

mBio ◽

10.1128/mbio.02089-17 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 12

Author(s):

Ryan M. Reddinger ◽

Nicole R. Luke-Marshall ◽

Shauna L. Sauberan ◽

Anders P. Hakansson ◽

Anthony A. Campagnari

Keyword(s):

Staphylococcus Aureus ◽

Streptococcus Pneumoniae ◽

Influenza A Virus ◽

Bacterial Pneumonia ◽

Influenza A ◽

Bacterial Species ◽

Invasive Disease ◽

Secondary Bacterial Pneumonia

ABSTRACTStreptococcus pneumoniaeandStaphylococcus aureusare ubiquitous upper respiratory opportunistic pathogens. Individually, these Gram-positive microbes are two of the most common causative agents of secondary bacterial pneumonia following influenza A virus infection, and they constitute a significant source of morbidity and mortality. Since the introduction of the pneumococcal conjugate vaccine, rates of cocolonization with both of these bacterial species have increased, despite the traditional view that they are antagonistic and mutually exclusive. The interactions betweenS. pneumoniaeandS. aureusin the context of colonization and the transition to invasive disease have not been characterized. In this report, we show thatS. pneumoniaeandS. aureusform stable dual-species biofilms on epithelial cellsin vitro. When these biofilms are exposed to physiological changes associated with viral infection,S. pneumoniaedisperses from the biofilm, whereasS. aureusdispersal is inhibited. These findings were supported by results of anin vivostudy in which we used a novel mouse cocolonization model. In these experiments, mice cocolonized in the nares with both bacterial species were subsequently infected with influenza A virus. The coinfected mice almost exclusively developed pneumococcal pneumonia. These results indicate that despite our previous report thatS. aureusdisseminates into the lungs of mice stably colonized with these bacteria following influenza A virus infection, cocolonization withS. pneumoniae in vitroandin vivoinhibitsS. aureusdispersal and transition to disease. This study provides novel insight into both the interactions betweenS. pneumoniaeandS. aureusduring carriage and the transition from colonization to secondary bacterial pneumonia.IMPORTANCEIn this study, we demonstrate thatStreptococcus pneumoniaecan modulate the pathogenic potential ofStaphylococcus aureusin a model of secondary bacterial pneumonia. We report that host physiological signals related to viral infection cease to elicit a dispersal response fromS. aureuswhile in a dual-species setting withS. pneumoniae, in direct contrast to results of previous studies with each species individually. This study underscores the importance of studying polymicrobial communities and their implications in disease states.

Download Full-text