Complications Among Adults Hospitalized With Influenza: A Comparison of Seasonal Influenza and the 2009 H1N1 Pandemic

ABSTRACTInfluenza virus hemagglutinin (HA) mediates virus entry by binding to cell surface receptors and fusing the viral and endosomal membranes following uptake by endocytosis. The acidic environment of endosomes triggers a large-scale conformational change in the transmembrane subunit of HA (HA2) involving a loop (B loop)-to-helix transition, which releases the fusion peptide at the HA2 N terminus from an interior pocket within the HA trimer. Subsequent insertion of the fusion peptide into the endosomal membrane initiates fusion. The acid stability of HA is influenced by residues in the fusion peptide, fusion peptide pocket, coiled-coil regions of HA2, and interactions between the surface (HA1) and HA2 subunits, but details are not fully understood and vary among strains. Current evidence suggests that the HA from the circulating pandemic 2009 H1N1 influenza A virus [A(H1N1)pdm09] is less stable than the HAs from other seasonal influenza virus strains. Here we show that residue 205 in HA1 and residue 399 in the B loop of HA2 (residue 72, HA2 numbering) in different monomers of the trimeric A(H1N1)pdm09 HA are involved in functionally important intermolecular interactions and that a conserved histidine in this pair helps regulate HA stability. An arginine-lysine pair at this location destabilizes HA at acidic pH and mediates fusion at a higher pH, while a glutamate-lysine pair enhances HA stability and requires a lower pH to induce fusion. Our findings identify key residues in HA1 and HA2 that interact to help regulate H1N1 HA stability and virus infectivity.IMPORTANCEInfluenza virus hemagglutinin (HA) is the principal antigen in inactivated influenza vaccines and the target of protective antibodies. However, the influenza A virus HA is highly variable, necessitating frequent vaccine changes to match circulating strains. Sequence changes in HA affect not only antigenicity but also HA stability, which has important implications for vaccine production, as well as viral adaptation to hosts. HA from the pandemic 2009 H1N1 influenza A virus is less stable than other recent seasonal influenza virus HAs, but the molecular interactions that contribute to HA stability are not fully understood. Here we identify molecular interactions between specific residues in the surface and transmembrane subunits of HA that help regulate the HA conformational changes needed for HA stability and virus entry. These findings contribute to our understanding of the molecular mechanisms controlling HA function and antigen stability.

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Viral surface geometry shapes influenza and coronavirus spike evolution through antibody pressure

10.1101/2020.10.20.347641 ◽

2020 ◽

Author(s):

Assaf Amitai

Keyword(s):

Antibody Response ◽

Computational Models ◽

Seasonal Influenza ◽

H1n1 Pandemic ◽

Surface Geometry ◽

Antigenic Sites ◽

2009 H1n1 ◽

Viral Surface ◽

Over Time ◽

Influenza H1n1

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the glycoprotein (spike). However, not all antigenic sites are targeted equally by antibodies, leading to complex immunodominance patterns. We used 3D computational models to estimate antibody pressure on the seasonal influenza H1N1 and SARS spikes. Analyzing publically available sequences, we show that antibody pressure, through the geometrical organization of spikes on the viral surface, shaped their mutability. Studying the mutability patterns of SARS-CoV-2 and the 2009 H1N1 pandemic spikes, we find that they are not predominantly shaped by antibody pressure. However, for SARS-CoV-2, we find that over time, it acquired mutations at antibody-accessible positions, which could indicate possible escape as define by our model. We offer a geometry-based approach to predict and rank the probability of surface resides of SARS-CoV-2 spike to acquire antibody escaping mutations.

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Lessons from the Past: Comparison of the Disease Burden of the Influenza A (H1N1) Pandemic 2009-10 and Seasonal Influenza 2010-2019 in the United States

10.21203/rs.3.rs-198743/v1 ◽

2021 ◽

Author(s):

James A Koziol

Keyword(s):

United States ◽

Influenza A ◽

Disease Burden ◽

Seasonal Influenza ◽

The United States ◽

H1n1 Pandemic ◽

Elderly Adults ◽

The Past ◽

Medical Visits ◽

Influenza A H1n1

Abstract Background Annual influenza outbreaks constitute a major public health concern, both in the United States and worldwide. Comparisons of the health burdens of outbreaks might lead to the identification of specific at-risk populations, for whom public health resources should be marshaled appropriately and equitably. Methods We examined the disease burden of the 2009-10 influenza A (H1N1) pandemic relating to illnesses, medical visits, hospitalizations, and mortality, compared to influenza seasons 2010 to 2019, in the United States, as compiled by the Centers for Disease Control. Results With regard to seasonal influenza, rates of illnesses and medical visits were highest in infants aged 0–4 years, followed by adults aged 50–64 years. Rates of hospitalizations and deaths evinced a starkly different pattern, both dominated by elderly adults aged 65 and over. Youths aged 0 to 17 years were especially adversely affected by the H1N1 pandemic relative to hospitalizations and mortality compared to seasonal influenza; but curiously the opposite pattern was observed in elderly adults (aged 65 and older). Conclusions The disease burden of the 2009-10 influenza A pandemic was strikingly unlike that observed in the subsequent influenza seasons 2010 to 2019, in the United States: the past did not predict the future.

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Comparison of characteristics of outpatients with 2009 H1N1 pandemic and seasonal influenza

International Journal of Clinical Practice ◽

10.1111/j.1742-1241.2011.02684.x ◽

2011 ◽

Vol 65 (8) ◽

pp. 871-878 ◽

Cited By ~ 3

Author(s):

G. Theocharis ◽

E. K. Vouloumanou ◽

S. G. Barbas ◽

T. Spiropoulos ◽

P. I. Rafailidis ◽

...

Keyword(s):

Seasonal Influenza ◽

H1n1 Pandemic ◽

2009 H1n1

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Comparative age distribution of influenza morbidity and mortality during seasonal influenza epidemics and the 2009 H1N1 pandemic

BMC Infectious Diseases ◽

10.1186/1471-2334-10-162 ◽

2010 ◽

Vol 10 (1) ◽

Cited By ~ 66

Author(s):

Magali Lemaitre ◽

Fabrice Carrat

Keyword(s):

Seasonal Influenza ◽

Age Distribution ◽

Morbidity And Mortality ◽

H1n1 Pandemic ◽

2009 H1n1

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Which Health Care Workers Were Most Affected During the Spring 2009 H1N1 Pandemic?

Disaster Medicine and Public Health Preparedness ◽

10.1017/s193578930000241x ◽

2010 ◽

Vol 4 (1) ◽

pp. 47-54 ◽

Cited By ~ 31

Author(s):

Cynthia D. Santos ◽

Robert B. Bristow ◽

Jaclyn V. Vorenkamp

Keyword(s):

Health Care ◽

Infection Rate ◽

Health Care Workers ◽

Influenza A ◽

Medical Personnel ◽

H1n1 Pandemic ◽

Infection Rates ◽

Hospital Employees ◽

Care Workers ◽

2009 H1n1

ABSTRACTObjectives: To identify health care workers most at risk for H1N1 infection before vaccination and compare health outcomes after vaccination.Methods: The indices used to gauge employee health were laboratory-confirmed H1N1 data, laboratory-confirmed influenza A data, and employee sick hours records. In phase 1 of this 2-phase study, absenteeism records for 6,093 hospital employees before vaccine administration were analyzed according to department and employee position during the spring 2009 H1N1 pandemic.Results: Records of 123 confirmed reports of laboratory-confirmed influenza A or novel H1N1 infections in hospital employees were also analyzed. Two thirds of the H1N1 cases occurred during June (infection rates in parentheses): 34 in physicians and medical personnel (6.7%), 36 in nurses and clinical technicians (2.2%), 39 in Administrative & Support Personnel (infection rate = 1.2%), 3 in Social Workers & Counselors (infection rate = 1.0%), 8 in Housekeeping & Food Services (infection rate = 2.7%), and 3 in Security & Transportation (infection rate=3.9%). When analyzed according to department, the adult emergency department (infection rate = 28.8%) and the pediatric emergency department (infection rate = 25.0%) had the highest infection rates per department.Conclusions: Of the reported cases of H1N1 in health care workers, 49% occurred in a population that constitutes less than 20% of the total population studied. Physicians and medical personnel had a higher infection rate than other employee positions, whereas ED personnel had the highest infection rate.(Disaster Med Public Health Preparedness. 2010;4:47-54)

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Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils

Journal of Virology ◽

10.1128/jvi.00817-15 ◽

2015 ◽

Vol 89 (17) ◽

pp. 8733-8748 ◽

Cited By ~ 13

Author(s):

Jeremy V. Camp ◽

Ulas Bagci ◽

Yong-Kyu Chu ◽

Brendan Squier ◽

Mostafa Fraig ◽

...

Keyword(s):

Respiratory Tract ◽

Influenza A Virus ◽

Lower Respiratory Tract ◽

Influenza A ◽

Live Imaging ◽

Host Responses ◽

H1n1 Pandemic ◽

Fdg Uptake ◽

Infection And Inflammation ◽

2009 H1n1

ABSTRACTInfection of the lower respiratory tract by influenza A viruses results in increases in inflammation and immune cell infiltration in the lung. The dynamic relationships among the lung microenvironments, the lung, and systemic host responses during infection remain poorly understood. Here we used extensive systematic histological analysis coupled with live imaging to gain access to these relationships in ferrets infected with the 2009 H1N1 pandemic influenza A virus (H1N1pdm virus). Neutrophil levels rose in the lungs of H1N1pdm virus-infected ferrets 6 h postinfection and became concentrated at areas of the H1N1pdm virus-infected bronchiolar epithelium by 1 day postinfection (dpi). In addition, neutrophil levels were increased throughout the alveolar spaces during the first 3 dpi and returned to baseline by 6 dpi. Histochemical staining revealed that neutrophil infiltration in the lungs occurred in two waves, at 1 and 3 dpi, and gene expression within microenvironments suggested two types of neutrophils. Specifically, CCL3 levels, but not CXCL8/interleukin 8 (IL-8) levels, were higher within discrete lung microenvironments and coincided with increased infiltration of neutrophils into the lung. We used live imaging of ferrets to monitor host responses within the lung over time with [18F]fluorodeoxyglucose (FDG). Sites in the H1N1pdm virus-infected ferret lung with high FDG uptake had high levels of proliferative epithelium. In summary, neutrophils invaded the H1N1pdm virus-infected ferret lung globally and focally at sites of infection. Increased neutrophil levels in microenvironments did not correlate with increased FDG uptake; hence, FDG uptake may reflect prior infection and inflammation of lungs that have experienced damage, as evidenced by bronchial regeneration of tissues in the lungs at sites with high FDG levels.IMPORTANCESevere influenza disease is characterized by an acute infection of the lower airways that may progress rapidly to organ failure and death. Well-developed animal models that mimic human disease are essential to understanding the complex relationships of the microenvironment, organ, and system in controlling virus replication, inflammation, and disease progression. Employing the ferret model of H1N1pdm virus infection, we used live imaging and comprehensive histological analyses to address specific hypotheses regarding spatial and temporal relationships that occur during the progression of infection and inflammation. We show the general invasion of neutrophils at the organ level (lung) but also a distinct pattern of localized accumulation within the microenvironment at the site of infection. Moreover, we show that these responses were biphasic within the lung. Finally, live imaging revealed an early and sustained host metabolic response at sites of infection that may reflect damage and repair of tissues in the lungs.

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