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. 2018 Jan 30;217(4):548-559.
doi: 10.1093/infdis/jix509.

Evidence for Viral Interference and Cross-reactive Protective Immunity Between Influenza B Virus Lineages

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Free PMC article

Evidence for Viral Interference and Cross-reactive Protective Immunity Between Influenza B Virus Lineages

Karen L Laurie et al. J Infect Dis. .
Free PMC article

Abstract

Background: Two influenza B virus lineages, B/Victoria and B/Yamagata, cocirculate in the human population. While the lineages are serologically distinct, cross-reactive responses to both lineages have been detected. Viral interference describes the situation whereby infection with one virus limits infection and replication of a second virus. We investigated the potential for viral interference between the influenza B virus lineages.

Methods: Ferrets were infected and then challenged 3, 10, or 28 days later with pairs of influenza B/Victoria and B/Yamagata viruses.

Results: Viral interference occurred at challenge intervals of 3 and 10 days and occasionally at 28 days. At the longer interval, shedding of challenge virus was reduced, and this correlated with cross-reactive interferon γ responses from lymph nodes from virus-infected animals. Viruses from both lineages could prevent or significantly limit subsequent infection with a virus from the other lineage. Coinfections were rare, indicating the potential for reassortment between lineages is limited.

Conclusions: These data suggest that innate and cross-reactive immunity mediate viral interference and that this may contribute to the dominance of a specific influenza B virus lineage in any given influenza season. Furthermore, infection with one influenza B virus lineage may be beneficial in protecting against subsequent infection with either influenza B virus lineage.

Keywords: Viral interference; cross-protection; dominance; ferret; influenza; influenza B; lineage.

Figures

Figure 1.
Figure 1.
Shedding of influenza B/Malaysia (B/Vic lineage; primary) and B/Florida (B/Yam lineage; challenge) viruses (A) and influenza B/Florida (primary) and B/Malaysia (challenge) viruses, with administration of primary and challenge viruses separated by 3 days. Real-time reverse-transcription polymerase chain reaction analysis was performed to detect the influenza B/Yam lineage hemagglutinin (HA) gene for B/Florida virus (solid blue) and the influenza B/Vic lineage HA gene for B/Malaysia virus (red stripes). Virus shedding for animals receiving challenge virus 3 days after primary virus is compared to shedding in respective control groups. Data are log10 copies per 100 μL of nasal wash. Dotted lines indicate limit of infectious virus.
Figure 2.
Figure 2.
Shedding of influenza B/Brisbane (B/Vic lineage; primary) and B/Massachusetts (B/Yam lineage; challenge) viruses (A) and influenza B/Massachusetts (primary) and B/Brisbane (challenge) viruses (B), with administration of primary and challenge viruses separated by 3 and 10 days. Reverse-transcription polymerase chain reaction analysis was performed to detect the influenza B/Yam lineage hemagglutinin (HA) gene for B/Massachusetts virus (solid blue) and the influenza B/Vic lineage HA gene for B/Brisbane virus (red stripes). Virus shedding for animals receiving challenge virus 3 and 10 days after primary virus is compared to shedding in respective control groups. Data are log10 copies per 100 μL of nasal wash. Dotted lines indicate limit of infectious virus.
Figure 3.
Figure 3.
Shedding of influenza B/Brisbane (B/Vic lineage; primary) and B/Phuket (B/Yam lineage; challenge) viruses (A) and influenza B/Phuket (primary) and B/Brisbane (challenge) viruses (B), with administration of primary and challenge viruses separated by 3 days. Real-time reverse-transcription polymerase chain reaction analysis was performed to detect the influenza B/Yam lineage hemagglutinin (HA) gene for B/Phuket virus (solid blue) and the influenza B/Vic lineage HA gene for B/Brisbane virus (red stripes). Virus shedding for animals receiving challenge virus 3 days after primary virus is compared to shedding in respective control groups. Data are log10 copies per 100 μL of nasal wash. Dotted lines indicate limit of infectious virus.
Figure 4.
Figure 4.
Prior infection with a different influenza B virus lineage can delay the start and reduce the duration of virus shedding. Kinetics of shedding was analyzed for all control ferrets and those receiving challenge virus 3 and 28 days after primary infection. AC, The number of days from challenge inoculation to the start of shedding of the challenge virus (A) and the number of days the challenge virus was shed (B and C) was determined for each ferret in the indicated groups. Lines indicate median values. D, The relationship between the duration of shedding of the challenge virus and the hemagglutination inhibition (HI) titer to the challenge virus was determined for all animals infected with the B/Brisbane and B/Phuket combination of viruses (A and B) by linear regression. CI, confidence interval.
Figure 5.
Figure 5.
Shedding of influenza B/Brisbane (B/Vic lineage; primary) and B/Massachusetts (B/Yam lineage; challenge) viruses (A) and influenza B/Massachusetts (primary) and B/Brisbane (challenge) viruses, with administration of primary and challenge viruses separated by 28 days. Real-time reverse-transcription polymerase chain reaction analysis was performed to detect the influenza B/Yam lineage hemagglutinin (HA) gene for B/Massachusetts virus (blue) and the influenza B/Vic lineage HA gene for B/Brisbane virus (red stripes). Virus shedding for animals receiving challenge virus 28 days after primary virus is compared to respective control groups. Data are log10 copies per 100 μL of nasal wash. Dotted lines indicate limit of infectious virus.
Figure 6.
Figure 6.
Infection with one influenza B virus lineage induces cross-reactive interferon γ (IFN-γ) responses to both influenza B virus lineages. A, Single-cell suspensions prepared from the lymph nodes of ferrets 3 or 10 days after infection with B/Massachusetts or A(H3N2) (A/Perth/16/2009) viruses were restimulated in vitro with live influenza virus. The number of IFN-γ–producing cells was determined by enzyme-linked immunospot (ELISpot) analysis. B, Lymph node cells were collected from a ferret infected with a B/Victoria virus and restimulated with influenza B or A(H3N2) viruses. After 48 hours, the cells were removed, messenger RNA was extracted and analyzed by quantitative polymerase chain reaction (qPCR) assays for IFN-γ, whereas the plate was stained for IFN-γ–producing cells by ELISpot. C, Lymph nodes were collected from animals 10 or 14 days after primary virus infection (white) or peripheral blood leukocytes were collected from animals 28 days after primary virus infection (black) and stimulated in vitro with virus, and the number of cells producing IFN-γ were determined by ELISpot. Each line represents a single ferret. Animals were infected with B/Brisbane or B/Massachusetts viruses, as indicated. D, The ratio of the number of spots produced to B/Brisbane to the number produced to B/Massachusetts for individual ferrets was determined.

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