Epidemiology and pathogenesis of influenza

Abstract Influenza A, B and C all have a segmented genome, although only certain influenza A subtypes and influenza B cause severe disease in humans. The two major proteins of influenza are the surface glycoproteins—haemagglutinin (HA) and neuraminidase (NA). HA is the major antigen for neutralizing antibodies and is involved in the binding of virus particles to receptors on host cells. Pandemics are a result of novel virus subtypes of influenza A, created by reassortment of the segmented genome (antigenic shift), whereas annual epidemics are a result of evolution of the surface antigens of influenza A and B virus (antigenic drift). The rapid evolution of influenza viruses highlights the importance of surveillance in identifying novel circulating strains. Infectivity of influenza depends on the cleavage of HA by specific host proteases, whereas NA is involved in the release of progeny virions from the cell surface and prevents clumping of newly formed virus. In birds, the natural hosts of influenza, the virus causes gastrointestinal infection and is transmitted via the faeco-oral route. Virulent avian influenza strains, which cause systemic disease, have an HA that is cleaved by proteases present in all cells of the body, rather than by proteases restricted to the intestinal tract. In mammals, replication of influenza subtypes appears restricted to respiratory epithelial cells. Most symptoms and complications, therefore, involve the respiratory tract. However, systemic complications are sometimes observed and other viral genes besides the HA, including the NA, may be involved in determination of virulence of influenza strains in mammals.

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Influenza

10.1093/med/9780198570028.003.0037 ◽

2011 ◽

Author(s):

D. J. Alexander ◽

N. Phin ◽

M. Zuckerman

Keyword(s):

Sialic Acid ◽

Human Population ◽

Influenza A ◽

Influenza Viruses ◽

Antigenic Drift ◽

Host Cells ◽

Influenza B Virus ◽

Influenza B ◽

Human Populations ◽

Influenza A Viruses

Influenza is a highly infectious, acute illness which has affected humans and animals since ancient times. Influenza viruses form the Orthomyxoviridae family and are grouped into types A, B, and C on the basis of the antigenic nature of the internal nucleocapsid or the matrix protein. Infl uenza A viruses infect a large variety of animal species, including humans, pigs, horses, sea mammals, and birds, occasionally producing devastating pandemics in humans, such as in 1918 when it has been estimated that between 50–100 million deaths occurred worldwide.There are two important viral surface glycoproteins, the haemagglutinin (HA) and neuraminidase (NA). The HA binds to sialic acid receptors on the membrane of host cells and is the primary antigen against which a host’s antibody response is targeted. The NA cleaves the sialic acid bond attaching new viral particles to the cell membrane of host cells allowing their release. The NA is also the target of the neuraminidase inhibitor class of antiviral agents that include oseltamivir and zanamivir and newer agents such as peramivir. Both these glycoproteins are important antigens for inducing protective immunity in the host and therefore show the greatest variation.Influenza A viruses are classified into 16 antigenically distinct HA (H1–16) and 9 NA subtypes (N1–9). Although viruses of relatively few subtype combinations have been isolated from mammalian species, all subtypes, in most combinations, have been isolated from birds. Each virus possesses one HA and one NA subtype.Last century, the sudden emergence of antigenically different strains in humans, termed antigenic shift, occurred on three occasions, 1918 (H1N1), 1957 (H2N2) and 1968 (H3N2), resulting in pandemics. The frequent epidemics that occur between the pandemics are as a result of gradual antigenic change in the prevalent virus, termed antigenic drift. Epidemics throughout the world occur in the human population due to infection with influenza A viruses, such as H1N1 and H3N2 subtypes, or with influenza B virus. Phylogenetic studies have led to the suggestion that aquatic birds that show no signs of disease could be the source of many influenza A viruses in other species. The 1918 H1N1 pandemic strain is thought to have arisen as a result of spontaneous mutations within an avian H1N1 virus. However, most pandemic strains, such as the 1957 H2N2, 1968 H3N2 and 2009 pandemic H1N1, are considered to have emerged by genetic re-assortment of the segmented RNA genome of the virus, with the avian and human influenza A viruses infecting the same host.Influenza viruses do not pass readily between humans and birds but transmission between humans and other animals has been demonstrated. This has led to the suggestion that the proposed reassortment of human and avian influenza viruses takes place in an intermediate animal with subsequent infection of the human population. Pigs have been considered the leading contender for the role of intermediary because they may serve as hosts for productive infections of both avian and human viruses, and there is good evidence that they have been involved in interspecies transmission of influenza viruses; particularly the spread of H1N1 viruses to humans. Apart from public health measures related to the rapid identification of cases and isolation. The main control measures for influenza virus infections in human populations involves immunization and antiviral prophylaxis or treatment.

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Molecular Characterization of Seasonal Influenza A and B from Hospitalized Patients in Thailand in 2018–2019

Viruses ◽

10.3390/v13060977 ◽

2021 ◽

Vol 13 (6) ◽

pp. 977

Author(s):

Kobporn Boonnak ◽

Chayasin Mansanguan ◽

Dennis Schuerch ◽

Usa Boonyuen ◽

Hatairat Lerdsamran ◽

...

Keyword(s):

Amino Acid ◽

Influenza A ◽

Seasonal Influenza ◽

Influenza Viruses ◽

Surface Proteins ◽

Antigenic Drift ◽

Influenza B ◽

Receptor Binding Site ◽

Antigenic Sites ◽

Ha Protein

Influenza viruses continue to be a major public health threat due to the possible emergence of more virulent influenza virus strains resulting from dynamic changes in virus adaptability, consequent of functional mutations and antigenic drift in surface proteins, especially hemagglutinin (HA) and neuraminidase (NA). In this study, we describe the genetic and evolutionary characteristics of H1N1, H3N2, and influenza B strains detected in severe cases of seasonal influenza in Thailand from 2018 to 2019. We genetically characterized seven A/H1N1 isolates, seven A/H3N2 isolates, and six influenza B isolates. Five of the seven A/H1N1 viruses were found to belong to clade 6B.1 and were antigenically similar to A/Switzerland/3330/2017 (H1N1), whereas two isolates belonged to clade 6B.1A1 and clustered with A/Brisbane/02/2018 (H1N1). Interestingly, we observed additional mutations at antigenic sites (S91R, S181T, T202I) as well as a unique mutation at a receptor binding site (S200P). Three-dimensional (3D) protein structure analysis of hemagglutinin protein reveals that this unique mutation may lead to the altered binding of the HA protein to a sialic acid receptor. A/H3N2 isolates were found to belong to clade 3C.2a2 and 3C.2a1b, clustering with A/Switzerland/8060/2017 (H3N2) and A/South Australia/34/2019 (H3N2), respectively. Amino acid sequence analysis revealed 10 mutations at antigenic sites including T144A/I, T151K, Q213R, S214P, T176K, D69N, Q277R, N137K, N187K, and E78K/G. All influenza B isolates in this study belong to the Victoria lineage. Five out of six isolates belong to clade 1A3-DEL, which relate closely to B/Washington/02/2009, with one isolate lacking the three amino acid deletion on the HA segment at position K162, N163, and D164. In comparison to the B/Colorado/06/2017, which is the representative of influenza B Victoria lineage vaccine strain, these substitutions include G129D, G133R, K136E, and V180R for HA protein. Importantly, the susceptibility to oseltamivir of influenza B isolates, but not A/H1N1 and A/H3N2 isolates, were reduced as assessed by the phenotypic assay. This study demonstrates the importance of monitoring genetic variation in influenza viruses regarding how acquired mutations could be associated with an improved adaptability for efficient transmission.

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The evolution of human influenza viruses

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2001.0999 ◽

2001 ◽

Vol 356 (1416) ◽

pp. 1861-1870 ◽

Cited By ~ 278

Author(s):

Alan J. Hay ◽

Victoria Gregory ◽

Alan R. Douglas ◽

Yi Pu Lin

Keyword(s):

Influenza A ◽

Influenza Viruses ◽

Antigenic Drift ◽

Influenza B ◽

Mixed Infections ◽

Human Influenza ◽

Influenza A Viruses ◽

Genetic Reassortment ◽

Influenza Ah1n1 ◽

Novel Influenza A

The evolution of influenza viruses results in (i) recurrent annual epidemics of disease that are caused by progressive antigenic drift of influenza A and B viruses due to the mutability of the RNA genome and (ii) infrequent but severe pandemics caused by the emergence of novel influenza A subtypes to which the population has little immunity. The latter characteristic is a consequence of the wide antigenic diversity and peculiar host range of influenza A viruses and the ability of their segmented RNA genomes to undergo frequent genetic reassortment (recombination) during mixed infections. Contrasting features of the evolution of recently circulating influenza AH1N1, AH3N2 and B viruses include the rapid drift of AH3N2 viruses as a single lineage, the slow replacement of successive antigenic variants of AH1N1 viruses and the co–circulation over some 25 years of antigenically and genetically distinct lineages of influenza B viruses. Constant monitoring of changes in the circulating viruses is important for maintaining the efficacy of influenza vaccines in combating disease.

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Establishment of pan-Influenza A (H1-H18) and pan-Influenza B (pre-split, Vic/Yam) Pseudotype Libraries for efficient vaccine antigen selection

10.1101/2021.05.20.444964 ◽

2021 ◽

Author(s):

Joanne M Del Rosario ◽

Kelly da Costa ◽

Benedikt Asbach ◽

Francesca Ferrara ◽

Matteo Ferrari ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Influenza A ◽

Influenza Viruses ◽

Vaccine Antigen ◽

Influenza Surveillance ◽

Influenza B ◽

Strategic Objectives ◽

Influenza Hemagglutinin ◽

Dosing Regimens

We have developed an influenza hemagglutinin (HA) pseudotype library encompassing Influenza A subtypes HA1-18, and Influenza B subtypes (both lineages) to be employed in influenza pseudotype microneutralization (pMN) assays. The pMN is highly sensitive and specific for de-tecting virus-specific neutralizing antibodies against influenza viruses and can be used to assess antibody functionality in vitro. Here we show the production of these viral HA pseudotypes and their employment as substitutes for wildtype viruses in influenza serological and neutralization assays. We demonstrate its utility in detecting serum response to vaccination with the ability to evaluate cross-subtype neutralizing responses elicited by specific vaccinating antigens. Our findings may inform further pre-clinical studies involving immunization dosing regimens in mice and may help in the creation and selection of better antigens for vaccine design. These HA pseudotypes can be harnessed to meet strategic objectives that contribute to the strengthening of global influenza surveillance, expansion of seasonal influenza prevention and control policies, and strengthening pandemic preparedness and response.

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Conserved structural RNA domains in regions coding for cleavage site motifs in hemagglutinin genes of influenza viruses

Virus Evolution ◽

10.1093/ve/vez034 ◽

2019 ◽

Vol 5 (2) ◽

Cited By ~ 4

Author(s):

Alexander P Gultyaev ◽

Mathilde Richard ◽

Monique I Spronken ◽

René C L Olsthoorn ◽

Ron A M Fouchier

Keyword(s):

Cleavage Site ◽

Influenza A ◽

Influenza Viruses ◽

Host Cells ◽

Influenza B ◽

Structural Constraints ◽

Highly Pathogenic ◽

Stem Loop ◽

Hairpin Loops ◽

Rna Domains

Abstract The acquisition of a multibasic cleavage site (MBCS) in the hemagglutinin (HA) glycoprotein is the main determinant of the conversion of low pathogenic avian influenza viruses into highly pathogenic strains, facilitating HA cleavage and virus replication in a broader range of host cells. In nature, substitutions or insertions in HA RNA genomic segments that code for multiple basic amino acids have been observed only in the HA genes of two out of sixteen subtypes circulating in birds, H5 and H7. Given the compatibility of MBCS motifs with HA proteins of numerous subtypes, this selectivity was hypothesized to be determined by the existence of specific motifs in HA RNA, in particular structured domains. In H5 and H7 HA RNAs, predictions of such domains have yielded alternative conserved stem-loop structures with the cleavage site codons in the hairpin loops. Here, potential RNA secondary structures were analyzed in the cleavage site regions of HA segments of influenza viruses of different types and subtypes. H5- and H7-like stem-loop structures were found in all known influenza A virus subtypes and in influenza B and C viruses with homology modeling. Nucleotide covariations supported this conservation to be determined by RNA structural constraints that are stronger in the domain-closing bottom stems as compared to apical parts. The structured character of this region in (sub-)types other than H5 and H7 indicates its functional importance beyond the ability to evolve toward an MBCS responsible for a highly pathogenic phenotype.

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Ode to Oseltamivir and Amantadine?

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2006/106989 ◽

2006 ◽

Vol 17 (1) ◽

pp. 11-14 ◽

Cited By ~ 5

Author(s):

JM Conly ◽

BL Johnston

Keyword(s):

Influenza A ◽

Antigenic Variation ◽

Interleukin 1 ◽

Influenza Viruses ◽

Host Cells ◽

Surface Glycoprotein ◽

Influenza B ◽

Influenza A Viruses ◽

Epidemic Disease ◽

Specific Antigens

Influenza A and B viruses are the two major types of influenza viruses that cause human epidemic disease. Influenza A viruses are further categorized into subtypes based on two surface antigens: hemagglutinin (H) and neuraminidase (N). Influenza B viruses are not categorized into subtypes (1). Influenza A viruses are found in many animal species, including humans, ducks, chickens, pigs, whales, horses and seals, whereas influenza B viruses circulate only among humans. The H antigen contains common and strain-specific antigens, demonstrates antigenic variation, and acts as a site of attachment of the virus to host cells to initiate infection (1). The N antigen contains subtype-specific antigens and also demonstrates antigenic variation between subtypes. It is a surface glycoprotein possessing enzymatic activity essential for viral replication in both influenza A and B viruses. The N antigen allows the release of newly produced virions from infected host cells, prevents the formation of viral aggregates after release from the host cells, and prevents viral inactivation by respiratory mucous (2,3). It is thought that this enzyme may also promote viral penetration into respiratory epithelial cells and may contribute to the pathogenicity of the virus by promoting production of proinflammatory cytokines such as interleukin-1 and tumour necrosis factor from macrophages (4-6).

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Serological studies of influenza viruses in pigs in Great Britain 1991–2

Epidemiology and Infection ◽

10.1017/s0950268800052225 ◽

1995 ◽

Vol 114 (3) ◽

pp. 511-520 ◽

Cited By ~ 31

Author(s):

I. H. Brown ◽

P. A. Harris ◽

D. J. Alexander

Keyword(s):

Great Britain ◽

Influenza A ◽

H1n1 Virus ◽

Haemagglutination Inhibition ◽

Influenza Viruses ◽

Antigenic Drift ◽

H3n2 Virus ◽

Influenza B Virus ◽

Influenza B ◽

Influenza A Viruses

SUMMARYSamples from a sow serum bank representative of the pig population of Great Britain collected during 1991–2, were examined for antibodies to influenza A, B and C viruses, using viruses which had been isolated from a variety of hosts. For influenza A viruses there was evidence of the continued circulation of ‘classical swine’ H1N1 virus (26%) seroprevalence), and human H3N2 viruses (39%) which are antigenically most closely-related to A/Port Chalmers/1/73 virus. In addition antibodies were detected to A/swine/England/201635/92 (8%), a strain of H3N2 virus which appears to have arisen by antigenic drift from conventional H3N2 swine strains. Specific antibodies (2%) were detected to an H1N1 virus (A/swine/England/195852/92) related most closely to avian H1N1 strains. In tests with human H1N1 and H3N2 viruses, excluding isolates from pigs, the highest seroprevalence was detected to the prevailing strains from the human population. Serological tests with avian H4 and H10, human H2, equine 1 and 2 influenza A viruses were all negative. Seven pigs seropositive by haemagglutination-inhibition, virus neutralization and immunoblotting assays for antibody to influenza B virus, were randomly distributed geographically suggesting that influenza B viruses may be transmitted to pigs but fail to spread. The seroprevalence to influenza C viruses was 9·9% indicating that these viruses are widespread in pigs. These results provide further evidence that the pig can be infected by a number of influenza viruses, some of which may have significance in the epidemiology of human influenza.

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Clinical and molecular epidemiology of influenza viruses from Romanian patients hospitalized during the 2019/20 season

PLoS ONE ◽

10.1371/journal.pone.0258798 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0258798

Author(s):

Victor Daniel Miron ◽

Leontina Bănică ◽

Oana Săndulescu ◽

Simona Paraschiv ◽

Marius Surleac ◽

...

Keyword(s):

Phylogenetic Analysis ◽

Vaccine Efficacy ◽

Influenza A ◽

Influenza Viruses ◽

Antigenic Drift ◽

Epidemiological Surveillance ◽

Influenza B Virus ◽

Influenza B ◽

Equal Distribution ◽

B Lineage

Two main mechanisms contribute to the continuous evolution of influenza viruses: accumulation of mutations in the hemagglutinin and neuraminidase genes (antigenic drift) and genetic re-assortments (antigenic shift). Epidemiological surveillance is important in identifying new genetic variants of influenza viruses with potentially increased pathogenicity and transmissibility. In order to characterize the 2019/20 influenza epidemic in Romania, 1042 respiratory samples were collected from consecutive patients hospitalized with acute respiratory infections in the National Institute for Infectious Diseases “Prof. Dr. Matei Balș”, Bucharest Romania and tested for influenza A virus, influenza B virus and respiratory syncytial virus (RSV) by real-time PCR. Out of them, 516 cases were positive for influenza, with relatively equal distribution of influenza A and B. Two patients had influenza A and B co-infection and 8 patients had influenza-RSV co-infection. The most severe cases, requiring supplemental oxygen administration or intensive care, and the most deaths were reported in patients aged 65 years and over. Subtyping showed the predominance of A(H3N2) compared to A(H1N1)pdm09 pdm09 (60.4% and 39.6% of all subtyped influenza A isolates, respectively), and the circulation of Victoria B lineage only. Influenza B started to circulate first (week 47/2019), with influenza A appearing slightly later (week 50/2019), followed by continued co-circulation of A and B viruses throughout the season. Sixty-eight samples, selected to cover the entire influenza season and all circulating viral types, were analysed by next generation sequencing (NGS). All A(H1N1)pdm09 sequences identified during this season in Romania were clustered in the 6b1.A clade (sub-clades: 6b1.A.183P -5a and 6b1.A.187A). For most A(H1N1)pdm09 sequences, the dominant epitope was Sb (pepitope = 0.25), reducing the vaccine efficacy by approximately 60%. According to phylogenetic analysis, influenza A(H3N2) strains circulating in this season belonged predominantly to clade 3C.3A, with only few sequences in clade 3C.2A1b. These 3C.2A1b sequences, two of which belonged to vaccinated patients, harbored mutations in antigenic sites leading to potential reduction of vaccine efficacy. Phylogenetic analysis of influenza B, lineage Victoria, sequences showed that the circulating strains belonged to clade V1A3. As compared to the other viral types, fewer mutations were observed in B/Victoria strains, with limited impact on vaccine efficiency based on estimations.

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INFLUENZA

JMS SKIMS ◽

10.33883/jms.v22i3.482 ◽

2019 ◽

Vol 22 (2) ◽

Author(s):

Syed Mudasir Qadri

Keyword(s):

Influenza A ◽

H1n1 Virus ◽

Acute Respiratory Tract Infection ◽

Influenza Viruses ◽

Antigenic Drift ◽

Influenza B ◽

Animal Reservoir ◽

Antigenic Shift ◽

Systemic Symptoms ◽

Global Population

Acute respiratory tract infection accompanying systemic symptoms are fever, malaise, coryza and myalgia. It is caused by influenza virus belonging to the orthomyxoviridae group. Three types of Influenza viruses occur in humans i.e. Influenza A, B and C All the known pandemics were caused by influenza A strains as it is known to change its genetic makeup by antigenic “shift” and “drift”. Influenza B is comparatively a genetically stable virus without any animal reservoir and Influenza C causes a milder disease. There is one more type, influenza D which occurs exclusively in cattle. The type A viruses are further divided into various subtypes based on the hemagglutinin “H” and neuraminidase “N” antigen expressed on their surface. There are 18 subtypes of hemagglutinin and 11 subtypes of neuraminidase. Influenza epidemics affect 10-20% of the global population on an average each year and are typically the result of minor antigenic variations of the virus or antigenic drift, which occur often in influenza A virus. On the other hand, pandemics which are associated with higher mortality appear at longer and varying intervals (often many decades) as a consequence of major genetic reassortment of the virus (antigenic shift) or adaptation of an avian or swine virus to humans (as with the pandemic H1N1 virus of 1918).

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Analysis of influenza A virus reinfection in children in Japan during 1983–91

Epidemiology and Infection ◽

10.1017/s0950268800058751 ◽

1995 ◽

Vol 115 (3) ◽

pp. 591-601 ◽

Cited By ~ 5

Author(s):

S. Nakajima ◽

F. Nishikawa ◽

K. Nakamura ◽

K. Nakajima

Keyword(s):

Amino Acid ◽

Influenza A Virus ◽

Influenza A ◽

Haemagglutination Inhibition ◽

Influenza Viruses ◽

Antigenic Drift ◽

H3n2 Virus ◽

Influenza B ◽

Influenza A H1n1 ◽

Influenza H3n2

SummaryThe epidemiology of influenza A in Japan was studied during 1979–91 and viruses isolated from reinfections during 1983–91 were analysed, Of 2963 influenza viruses isolated during this period, 922 and 1006 were influenza A(H1N1) and A(H3N2) viruses respectively; the others were influenza B viruses. Influenza A(H1N1) and A(H3N2) caused 5 and 6 epidemics respectively, most accompanied by antigenic drift. Seventeen reinfections with H1N1 and 17 with H3N2 were detected during our study. The primary and reinfection strains isolated from 7 H1N1 and 10 H3N2 cases were studied by haemagglutination-inhibition, and amino acid and nucleotide sequences of the HA1 region of the haemagglutinin. Most of the primary and reinfection strains were antigenically and genetically similar to the epidemic viruses circulating at that time. However, in 4 out of 10 cases of reinfection with influenza H3N2 virus, reinfection strains were genetically different from the epidemic viruses.

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