scholarly journals A Perfect Storm: Increased Colonization and Failure of Vaccination Leads to Severe Secondary Bacterial Infection in Influenza Virus-Infected Obese Mice

mBio ◽  
2017 ◽  
Vol 8 (5) ◽  
Author(s):  
Erik A. Karlsson ◽  
Victoria A. Meliopoulos ◽  
Nicholas C. van de Velde ◽  
Lee-Ann van de Velde ◽  
Beth Mann ◽  
...  
Keyword(s):  
Public Health ◽  
Influenza Virus ◽  
Virus Infection ◽  
Bacterial Infection ◽  
Antibiotic Treatment ◽  
Influenza Virus Infection ◽  
Health Concern ◽  
Obese Mice ◽  
Secondary Bacterial Infection ◽  
Perfect Storm

ABSTRACT Obesity is a risk factor for developing severe disease following influenza virus infection; however, the comorbidity of obesity and secondary bacterial infection, a serious complication of influenza virus infections, is unknown. To fill this gap in knowledge, lean and obese C57BL/6 mice were infected with a nonlethal dose of influenza virus followed by a nonlethal dose of Streptococcus pneumoniae. Strikingly, not only did significantly enhanced death occur in obese coinfected mice compared to lean controls, but also high mortality was seen irrespective of influenza virus strain, bacterial strain, or timing of coinfection. This result was unexpected, given that most influenza virus strains, especially seasonal human A and B viruses, are nonlethal in this model. Both viral and bacterial titers were increased in the upper respiratory tract and lungs of obese animals as early as days 1 and 2 post-bacterial infection, leading to a significant decrease in lung function. This increased bacterial load correlated with extensive cellular damage and upregulation of platelet-activating factor receptor, a host receptor central to pneumococcal invasion. Importantly, while vaccination of obese mice against either influenza virus or pneumococcus failed to confer protection, antibiotic treatment was able to resolve secondary bacterial infection-associated mortality. Overall, secondary bacterial pneumonia could be a widespread, unaddressed public health problem in an increasingly obese population. IMPORTANCE Worldwide obesity rates have continued to increase. Obesity is associated with increased severity of influenza virus infection; however, very little is known about respiratory coinfections in this expanding, high-risk population. Our studies utilized a coinfection model to show that obesity increases mortality from secondary bacterial infection following influenza virus challenge through a “perfect storm” of host factors that lead to excessive viral and bacterial outgrowth. In addition, we found that vaccination of obese mice against either virus or bacteria failed to confer protection against coinfection, but antibiotic treatment did alleviate mortality. Combined, these results represent an understudied and imminent public health concern in a weighty portion of the global population. IMPORTANCE Worldwide obesity rates have continued to increase. Obesity is associated with increased severity of influenza virus infection; however, very little is known about respiratory coinfections in this expanding, high-risk population. Our studies utilized a coinfection model to show that obesity increases mortality from secondary bacterial infection following influenza virus challenge through a “perfect storm” of host factors that lead to excessive viral and bacterial outgrowth. In addition, we found that vaccination of obese mice against either virus or bacteria failed to confer protection against coinfection, but antibiotic treatment did alleviate mortality. Combined, these results represent an understudied and imminent public health concern in a weighty portion of the global population.

scholarly journals Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Kari Ann Shirey ◽  
Darren J. Perkins ◽  
Wendy Lai ◽  
Wei Zhang ◽  
Lurds R. Fernando ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Bacterial Infection ◽  
Bacterial Infections ◽  
Influenza Virus Infection ◽  
Health Concern ◽  
Type I ◽  
Lung Pathology ◽  
Chemokine Production ◽  
Content Type

ABSTRACT We previously reported that the Toll-like receptor 4 (TLR4) antagonist Eritoran blocks acute lung injury (ALI) therapeutically in mouse and cotton rat models of influenza. However, secondary (2°) bacterial infection following influenza virus infection is associated with excess morbidity and mortality. Wild-type (WT) mice infected with mouse-adapted influenza A/Puerto Rico/8/34 virus (PR8) and, 7 days later, with Streptococcus pneumoniae serotype 3 (Sp3) exhibited significantly enhanced lung pathology and lethality that was reversed by Eritoran therapy after PR8 infection but before Sp3 infection. Cotton rats infected with nonadapted pH1N1 influenza virus and then superinfected with methicillin-resistant Staphylococcus aureus also exhibited increased lung pathology and serum high-mobility-group box 1 (HMGB1) levels, both of which were blunted by Eritoran therapy. In mice, PR8 infection suppressed Sp3-induced CXCL1 and CXCL2 mRNA, reducing neutrophil infiltration and increasing the bacterial burden, all of which were reversed by Eritoran treatment. While beta interferon (IFN-β)-deficient (IFN-β−/−) mice are highly susceptible to PR8, they exhibited delayed death upon Sp3 superinfection, indicating that while IFN-β was protective against influenza, it negatively impacted the host response to Sp3. IFN-β-treated WT macrophages selectively suppressed Sp3-induced CXCL1/CXCL2 transcriptionally, as evidenced by reduced recruitment of RNA polymerase II to the CXCL1 promoter. Thus, influenza establishes a “trained” state of immunosuppression toward 2° bacterial infection, in part through the potent induction of IFN-β and its downstream transcriptional regulation of chemokines, an effect reversed by Eritoran. IMPORTANCE Enhanced susceptibility to 2° bacterial infections following infection with influenza virus is a global health concern that accounts for many hospitalizations and deaths, particularly during pandemics. The complexity of the impaired host immune response during 2° bacterial infection has been widely studied. Both type I IFN and neutrophil dysfunction through decreased chemokine production have been implicated as mechanisms underlying enhanced susceptibility to 2° bacterial infections. Our findings support the conclusion that selective suppression of CXCL1/CXCL2 represents an IFN-β-mediated “training” of the macrophage transcriptional response to TLR2 agonists and that blocking of TLR4 therapeutically with Eritoran after influenza virus infection reverses this suppression by blunting influenza-induced IFN-β.

scholarly journals 1H NMR-Based Profiling Reveals Differential Immune-Metabolic Networks during Influenza Virus Infection in Obese Mice

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e97238 ◽  
Author(s):  
J. Justin Milner ◽  
Jue Wang ◽  
Patricia A. Sheridan ◽  
Tim Ebbels ◽  
Melinda A. Beck ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
1H Nmr ◽  
Metabolic Networks ◽  
Influenza Virus Infection ◽  
Obese Mice

scholarly journals Defining the kinetic effects of infection with influenza virus A/PR8/34 (H1N1) on sphingosine-1-phosphate signaling in mice by targeted LC/MS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Divyavani Gowda ◽  
Marumi Ohno ◽  
Siddabasave Gowda B. Gowda ◽  
Hitoshi Chiba ◽  
Masashi Shingai ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Health Concern ◽  
Biological Responses ◽  
Novel Drugs ◽  
Associated Symptoms ◽  
Sphingosine 1 Phosphate ◽  
Kinetic Effects ◽  
S1p Lyase

AbstractInfluenza remains a world-wide health concern, causing 290,000–600,000 deaths and up to 5 million cases of severe illnesses annually. Noticing the host factors that control biological responses, such as inflammatory cytokine secretion, to influenza virus infection is important for the development of novel drugs. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite and has essential biological functions in inflammation. However, the kinetic effects of influenza virus infection on physiological S1P levels and their signaling in multiple tissues remain unknown. In this study, we utilized a mouse model intranasally infected with 50 or 500 plaque forming units (PFU) of A/Puerto Rico/8/34 (H1N1; PR8) virus to investigate how S1P levels and expression of its regulating factors are affected by influenza virus infection by the liquid-chromatography/mass spectrometry and real-time PCR, respectively. The S1P level was significantly high in the plasma of mice infected with 500 PFU of the virus than that in control mice at 6 day-post-infection (dpi). Elevated gene expression of sphingosine kinase-1 (Sphk1), an S1P synthase, was observed in the liver, lung, white adipose tissue, heart, and aorta of infected mice. This could be responsible for the increased plasma S1P levels as well as the decrease in the hepatic S1P lyase (Sgpl1) gene in the infected mice. These results indicate modulation of S1P-signaling by influenza virus infection. Since S1P regulates inflammation and leukocyte migration, it must be worth trying to target this signaling to control influenza-associated symptoms.

scholarly journals THE INFLUENCE OF INFLUENZA VIRUS INFECTION ON EXOGENOUS STAPHYLOCOCCAL AND ENDOGENOUS MURINE BACTERIAL INFECTION OF THE BRONCHOPULMONARY TISSUES OF MICE

1961 ◽  
Vol 114 (2) ◽  
pp. 237-256 ◽  
Author(s):  
Thomas F. Sellers ◽  
Jerome Schulman ◽  
Claude Bouvier ◽  
Robert McCune ◽  
Edwin D. Kilbourne
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Respiratory Tract ◽  
Bacterial Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Defense Mechanisms ◽  
Influenza Virus Infection ◽  
Asian Strain ◽  
Temporary Inhibition

Mice infected with a non-mouse-adapted Asian strain of influenza A virus suffered an impaired capacity to destroy or remove staphylococci introduced by the respiratory route. This temporary inhibition of local defense mechanisms was of 7 to 10 days' duration. The persistence of staphylococci in the lung following influenza did not appear to alter the nature of the pathologic reaction to influenza virus. The presence of influenza virus infection in the respiratory tract of the mouse did not alter the fate of intravenous staphylococci in the lung or other organs. In 40 to 50 per cent of mice with influenza, purulent bronchopneumonia and infection with Pasteurella and Hemophilus of murine origin were noted. A minority of control animals evidenced such infection. The administration of antimicrobials to which the murine bacteria were susceptible prevented both the appearance of the endogenous infection with Pasteurella or Hemophilus and the purulent sequelae to influenza virus infection. The true picture of uncomplicated bronchopulmonary influenza virus infection was thus separated from the combined virus-bacteria effect otherwise encountered.

scholarly journals Modelling within-host macrophage dynamics in influenza virus infection

2020 ◽  
Author(s):  
Ke Li ◽  
James M. McCaw ◽  
Pengxing Cao
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Viral Infection ◽  
Dynamic Model ◽  
Macrophage Activation ◽  
Negative Relationship ◽  
Influenza Virus Infection ◽  
Health Concern ◽  
Viral Shedding ◽  
Excessive Accumulation

AbstractHuman respiratory disease associated with influenza virus infection is of significant public health concern. Macrophages, as part of the front line of host innate cellular defence, have been shown to play an important role in controlling viral replication. However, fatal outcomes of infection, as evidenced in patients infected with highly pathogenic viral strains, are often associated with prompt activation and excessive accumulation of macrophages. Activated macrophages can produce a large amount of pro-inflammatory cytokines, which leads to severe symptoms and at times death. However, the mechanism for rapid activation and excessive accumulation of macrophages during infection remains unclear. It has been suggested that the phenomena may arise from complex interactions between macrophages and influenza virus. In this work, we develop a novel mathematical model to study the relationship between the level of macrophage activation and the level of viral shedding in influenza virus infection. Our model combines a dynamic model of viral infection, a dynamic model of macrophages and the essential interactions between the virus and macrophages. Our model predicts that the level of macrophage activation can be negatively correlated with the level of viral shedding when viral infectivity is sufficiently high. We further identify that temporary depletion of resting macrophages in response to viral infection is a major driver in our model for the negative relationship between macrophage activation and viral shedding, providing new insight into the mechanisms that regulate macrophage activation. Our model serves as a framework to study the complex dynamics of virus-macrophage interactions and provides a mechanistic explanation for existing experimental observations, contributing to an enhanced understanding of the role of macrophages in influenza viral infection.

scholarly journals Vaccination protects obese mice from morbidity and mortality associated with influenza virus infection

2006 ◽  
Vol 20 (5) ◽  
Author(s):  
Erik A Karlsson ◽  
Alexia G Smith ◽  
Patricia A Sheridan ◽  
Melinda A Beck
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Morbidity And Mortality ◽  
Obese Mice

scholarly journals Obesity Outweighs Protection Conferred by Adjuvanted Influenza Vaccination

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Erik A. Karlsson ◽  
Tomer Hertz ◽  
Cydney Johnson ◽  
Andrew Mehle ◽  
Florian Krammer ◽  
...  
Keyword(s):  
Public Health ◽  
Influenza Virus ◽  
High Risk ◽  
Influenza Virus Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Obese Mice ◽  
Virus Challenge ◽  
Obesity Epidemic ◽  
Antibody Levels

ABSTRACT Obesity is a risk factor for developing severe influenza virus infection, making vaccination of utmost importance for this high-risk population. However, vaccinated obese animals and adults have decreased neutralizing antibody responses. In these studies, we tested the hypothesis that the addition of either alum or a squalene-based adjuvant (AS03) to an influenza vaccine would improve neutralizing antibody responses and protect obese mice from challenge. Our studies demonstrate that adjuvanted vaccine does increase both neutralizing and nonneutralizing antibody levels compared to vaccine alone. Although obese mice mount significantly decreased virus-specific antibody responses, both the breadth and the magnitude of the responses against hemagglutinin (HA) and neuraminidase (NA) are decreased compared to the responses in lean mice. Importantly, even with a greater than fourfold increase in neutralizing antibody levels, obese mice are not protected against influenza virus challenge and viral loads remain elevated in the respiratory tract. Increasing the antigen dose affords no added protection, and a decreasing viral dose did not fully mitigate the increased mortality seen in obese mice. Overall, these studies highlight that, while the use of an adjuvant does improve seroconversion, vaccination does not fully protect obese mice from influenza virus challenge, possibly due to the increased sensitivity of obese animals to infection. Given the continued increase in the global obesity epidemic, our findings have important implications for public health. IMPORTANCE Vaccination is the most effective strategy for preventing influenza virus infection and is a key component for pandemic preparedness. However, vaccines may fail to provide optimal protection in high-risk groups, including overweight and obese individuals. Given the worldwide obesity epidemic, it is imperative that we understand and improve vaccine efficacy. No work to date has investigated whether adjuvants increase the protective capacity of influenza vaccines in the obese host. In these studies, we show that adjuvants increased the neutralizing and nonneutralizing antibody responses during vaccination of lean and obese mice to levels considered “protective,” and yet, obese mice still succumbed to infection. This vulnerability is likely due to a combination of factors, including the increased susceptibility of obese animals to develop severe and even lethal disease when infected with very low viral titers. Our studies highlight the critical public health need to translate these findings and better understand vaccination in this increasing population.

scholarly journals Impaired Wound Healing Predisposes Obese Mice to Severe Influenza Virus Infection

2011 ◽  
Vol 205 (2) ◽  
pp. 252-261 ◽  
Author(s):  
Kevin B. O’Brien ◽  
Peter Vogel ◽  
Susu Duan ◽  
Elena A. Govorkova ◽  
Richard J. Webby ◽  
...  
Keyword(s):  
Wound Healing ◽  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Obese Mice ◽  
Impaired Wound Healing ◽  
Severe Influenza

scholarly journals Absence of β6 Integrin Reduces Influenza Disease Severity in Highly Susceptible Obese Mice

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Victoria Meliopoulos ◽  
Brandi Livingston ◽  
Lee-Ann Van de Velde ◽  
Rebekah Honce ◽  
Stacey Schultz-Cherry
Keyword(s):  
Influenza Virus ◽  
High Risk ◽  
Virus Infection ◽  
Disease Severity ◽  
Influenza Virus Infection ◽  
Obese Mouse ◽  
Type I ◽  
Type I Ifn ◽  
Obese Mice ◽  
Viral Spread

ABSTRACT Obese individuals are considered a high-risk group for developing severe influenza virus infection. While the exact mechanisms for increased disease severity remain under investigation, obese-mouse models suggest that increased acute lung injury (ALI), potentially due to enhanced viral spread and decreased wound repair, is likely involved. We previously demonstrated that upregulation of the lung epithelial cell β6 integrin during influenza virus infection was involved in disease severity. Knocking out β6 (β6 KO) resulted in improved survival. Of interest, obese mice have increased lung β6 integrin levels at homeostasis. Thus, we hypothesized that the protective effect seen in β6 KO mice would extend to the highly susceptible obese-mouse model. In the current study, we show that crossing β6 KO mice with genetically obese (ob/ob) mice (OBKO) resulted in reduced ALI and impaired viral spread, like their lean counterparts. Mechanistically, OBKO alveolar macrophages and epithelial cells had increased type I interferon (IFN) signaling, potentially through upregulated type I IFN receptor expression, which was important for the enhanced protection during infection. Taken together, our results indicate that the absence of an epithelial integrin can beneficially alter the pulmonary microenvironment by increasing protective type I IFN responses even in a highly susceptible obese-mouse model. These studies increase our understanding of influenza virus pathogenesis in high-risk populations and may lead to the development of novel therapies. IMPORTANCE Obesity is a risk factor for developing severe influenza virus infection. However, the reasons for this are unknown. We found that the lungs of obese mice have increased expression of the epithelial integrin β6, a host factor associated with increased disease severity. Knocking out integrin β6 in obese mice favorably altered the pulmonary environment by increasing type I IFN signaling, resulting in decreased viral spread, reduced lung injury, and increased survival. This study furthers our understanding of influenza virus pathogenesis in the high-risk obese population and may potentially lead to the development of novel therapies for influenza virus infection.

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