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

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.

Download Full-text

Discrete Dynamical Modeling of Influenza Virus Infection Suggests Age-Dependent Differences in Immunity

Journal of Virology ◽

10.1128/jvi.00395-17 ◽

2017 ◽

Vol 91 (23) ◽

Cited By ~ 2

Author(s):

Ericka Keef ◽

Li Ang Zhang ◽

David Swigon ◽

Alisa Urbano ◽

G. Bard Ermentrout ◽

...

Keyword(s):

Immune Response ◽

Influenza Virus ◽

Virus Infection ◽

Immune Responses ◽

Influenza Virus Infection ◽

The Elderly ◽

Morbidity And Mortality ◽

Age Group ◽

Rule Based ◽

Delayed Onset

ABSTRACT Immunosenescence, an age-related decline in immune function, is a major contributor to morbidity and mortality in the elderly. Older hosts exhibit a delayed onset of immunity and prolonged inflammation after an infection, leading to excess damage and a greater likelihood of death. Our study applies a rule-based model to infer which components of the immune response are most changed in an aged host. Two groups of BALB/c mice (aged 12 to 16 weeks and 72 to 76 weeks) were infected with 2 inocula: a survivable dose of 50 PFU and a lethal dose of 500 PFU. Data were measured at 10 points over 19 days in the sublethal case and at 6 points over 7 days in the lethal case, after which all mice had died. Data varied primarily in the onset of immunity, particularly the inflammatory response, which led to a 2-day delay in the clearance of the virus from older hosts in the sublethal cohort. We developed a Boolean model to describe the interactions between the virus and 21 immune components, including cells, chemokines, and cytokines, of innate and adaptive immunity. The model identifies distinct sets of rules for each age group by using Boolean operators to describe the complex series of interactions that activate and deactivate immune components. Our model accurately simulates the immune responses of mice of both ages and with both inocula included in the data (95% accurate for younger mice and 94% accurate for older mice) and shows distinct rule choices for the innate immunity arm of the model between younger and aging mice in response to influenza A virus infection. IMPORTANCE Influenza virus infection causes high morbidity and mortality rates every year, especially in the elderly. The elderly tend to have a delayed onset of many immune responses as well as prolonged inflammatory responses, leading to an overall weakened response to infection. Many of the details of immune mechanisms that change with age are currently not well understood. We present a rule-based model of the intrahost immune response to influenza virus infection. The model is fit to experimental data for young and old mice infected with influenza virus. We generated distinct sets of rules for each age group to capture the temporal differences seen in the immune responses of these mice. These rules describe a network of interactions leading to either clearance of the virus or death of the host, depending on the initial dosage of the virus. Our models clearly demonstrate differences in these two age groups, particularly in the innate immune responses.

Download Full-text

Vaccination with Adjuvanted Recombinant Neuraminidase Induces Broad Heterologous, but Not Heterosubtypic, Cross-Protection against Influenza Virus Infection in Mice

mBio ◽

10.1128/mbio.02556-14 ◽

2015 ◽

Vol 6 (2) ◽

Cited By ~ 87

Author(s):

Teddy John Wohlbold ◽

Raffael Nachbagauer ◽

Haoming Xu ◽

Gene S. Tan ◽

Ariana Hirsh ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza Vaccine ◽

Influenza Virus Infection ◽

Morbidity And Mortality ◽

Vaccine Antigen ◽

Influenza B Virus ◽

Influenza B ◽

Protective Potential ◽

The Cross

ABSTRACTIn an attempt to assess the cross-protective potential of the influenza virus neuraminidase (NA) as a vaccine antigen, different subtypes of recombinant NA were expressed in a baculovirus system and used to vaccinate mice prior to lethal challenge with homologous, heterologous, or heterosubtypic viruses. Mice immunized with NA of subtype N2 were completely protected from morbidity and mortality in a homologous challenge and displayed significantly reduced viral lung titers. Heterologous challenge with a drifted strain resulted in morbidity but no mortality. Similar results were obtained for challenge experiments with N1 NA. Mice immunized with influenza B virus NA (from B/Yamagata/16/88) displayed no morbidity when sublethally infected with the homologous strain and, importantly, were completely protected from morbidity and mortality when lethally challenged with the prototype Victoria lineage strain or a more recent Victoria lineage isolate. Upon analyzing the NA content in 4 different inactivated-virus vaccine formulations from the 2013-2014 season via Western blot assay and enzyme-linked immunosorbent assay quantification, we found that the amount of NA does indeed vary across vaccine brands. We also measured hemagglutinin (HA) and NA endpoint titers in pre- and postvaccination human serum samples from individuals who received a trivalent inactivated seasonal influenza vaccine from the 2004-2005 season; the induction of NA titers was statistically less pronounced than the induction of HA titers. The demonstrated homologous and heterologous protective capacity of recombinant NA suggests that supplementing vaccine formulations with a standard amount of NA may offer increased protection against influenza virus infection.IMPORTANCEDespite the existence of vaccine prophylaxis and antiviral therapeutics, the influenza virus continues to cause morbidity and mortality in the human population, emphasizing the continued need for research in the field. While the majority of influenza vaccine strategies target the viral hemagglutinin, the immunodominant antigen on the surface of the influenza virion, antibodies against the viral neuraminidase (NA) have been correlated with less severe disease and decreased viral shedding in humans. Nevertheless, the amount of NA is not standardized in current seasonal vaccines, and the exact breadth of NA-based protection is unknown. Greater insight into the cross-protective potential of influenza virus NA as a vaccine antigen may pave the way for the development of influenza vaccines of greater breadth and efficacy.

Download Full-text

Hemagglutinin Stalk- and Neuraminidase-Specific Monoclonal Antibodies Protect against Lethal H10N8 Influenza Virus Infection in Mice

Journal of Virology ◽

10.1128/jvi.02275-15 ◽

2015 ◽

Vol 90 (2) ◽

pp. 851-861 ◽

Cited By ~ 38

Author(s):

Teddy John Wohlbold ◽

Veronika Chromikova ◽

Gene S. Tan ◽

Philip Meade ◽

Fatima Amanat ◽

...

Keyword(s):

Influenza Virus ◽

Monoclonal Antibodies ◽

Virus Infection ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Morbidity And Mortality ◽

Head Domain ◽

Group 2 ◽

Reactive Antibody ◽

Globular Head

ABSTRACTBetween November 2013 and February 2014, China reported three human cases of H10N8 influenza virus infection in the Jiangxi province, two of which were fatal. Using hybridoma technology, we isolated a panel of H10- and N8-directed monoclonal antibodies (MAbs) and further characterized the binding reactivity of these antibodies (via enzyme-linked immunosorbent assay) to a range of purified virus and recombinant protein substrates. The H10-directed MAbs displayed functional hemagglutination inhibition (HI) and neutralization activity, and the N8-directed antibodies displayed functional neuraminidase inhibition (NI) activity against H10N8. Surprisingly, the HI-reactive H10 antibodies, as well as a previously generated, group 2 hemagglutinin (HA) stalk-reactive antibody, demonstrated NI activity against H10N8 and an H10N7 strain; this phenomenon was absent when virus was treated with detergent, suggesting the anti-HA antibodies inhibited neuraminidase enzymatic activity through steric hindrance. We tested the prophylactic efficacy of one representative H10-reactive, N8-reactive, and group 2 HA stalk-reactive antibodyin vivousing a BALB/c challenge model. All three antibodies were protective at a high dose (5 mg/kg). At a low dose (0.5 mg/kg), only the anti-N8 antibody prevented weight loss. Together, these data suggest that antibody targets other than the globular head domain of the HA may be efficacious in preventing influenza virus-induced morbidity and mortality.IMPORTANCEAvian H10N8 and H10N7 viruses have recently crossed the species barrier, causing morbidity and mortality in humans and other mammals. Although these reports are likely isolated incidents, it is possible that more cases may emerge in future winter seasons, similar to H7N9. Furthermore, regular transmission of avian influenza viruses to humans increases the risk of adaptive mutations and reassortment events, which may result in a novel virus with pandemic potential. Currently, no specific therapeutics or vaccines are available against the H10N8 influenza virus subtype. We generated a panel of H10- and N8-reactive MAbs. Although these antibodies may practically be developed into therapeutic agents, characterizing the protective potential of MAbs that have targets other than the HA globular head domain will provide insight into novel antibody-mediated mechanisms of protection and help to better understand correlates of protection for influenza A virus infection.

Download Full-text

Impaired Wound Healing Predisposes Obese Mice to Severe Influenza Virus Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jir729 ◽

2011 ◽

Vol 205 (2) ◽

pp. 252-261 ◽

Cited By ~ 60

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

Download Full-text

Assessement of the influenza burden in nursing homes during two influenza seasons

European Journal of Public Health ◽

10.1093/eurpub/ckz187.073 ◽

2019 ◽

Vol 29 (Supplement_4) ◽

Author(s):

L Qalla-Widmer ◽

C Petignat

Keyword(s):

Influenza Virus ◽

Nursing Homes ◽

Virus Infection ◽

Influenza Vaccination ◽

Healthcare Workers ◽

Influenza Season ◽

Influenza Virus Infection ◽

Morbidity And Mortality ◽

Influenza Like Illness ◽

Vaccination Rates

Abstract Influenza is a significant cause of morbidity and mortality in elderly. They are at high risk of complications after influenza virus infection. Data on the epidemiology of influenza within nursing homes (NH) are limited. The purpose of this prospective study was to better describe the burden of influenza among residents of NH of canton of Vaud, Switzerland, with influenza-like illness during 2016-2017 and 2017-2018 influenza seasons. First, we determined the proportion of influenza-like illness due to influenza in NH residents. We specifically assessed the impact of a positive influenza PCR on clinical features, morbidity and mortality, 30 and 90 days after diagnosis, as compared to a negative influenza PCR. Moreover, influenza vaccination rates of the residents and the healthcare workers within each nursing home were assessed at the end of each influenza season. A PCR test was performed on 509 residents from 61 NH. 227 influenza virus infections were diagnosed; 181 influenza A and 46 influenza B. Compared to residents without influenza virus infection (IVI), residents with IVI were more often feverish with a high fever (69.1% and 88.5% respectively, p < 0.0001) are significantly more frequently hospitalized within 30 days after diagnosis (17.6% vs 7.1%, p = 0.0003). Any cause mortality at 30 days was similar in both groups (12.8% vs 10.6%, p = 0.48). Only 18.1% of IVI residents were treated with an antiviral and 60.4% of them received antibiotics. Influenza vaccination rates of the healthcare workers and residents were respectively 50% and 82%. During influenza season, the feverish residents should be suspected to have influenza virus infection. Residents should be diagnosed (PCR) and treated with an antiviral where appropriate to limit the risk of hospitalization. Healthcare workers should be encouraged to be vaccinated against influenza in order to acquire a better herd immunity within the NH which will limit the spread of influenza. Key messages Influenza virus in nursing homes is not treated enough. Influenza virus infection in nursing homes causes a high number of hospitalizations.

Download Full-text

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

Journal of Virology ◽

10.1128/jvi.01646-18 ◽

2018 ◽

Vol 93 (2) ◽

Cited By ~ 3

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.

Download Full-text