Differential effects of influenza virus NA, HA head, and HA stalk antibodies on peripheral blood leukocyte gene expression during human infection

Kathie Anne Walters, Ruoqing Zhu, Michael Welge, Kelsey Scherler, Jae Keun Park, Zainab Rahil, Hao Wang, Loretta Auvil, Colleen Bushell, Min Young Lee, David Baxter, Tyler Bristol, Luz Angela Rosas, Adriana Cervantes-Medina, Lindsay Czajkowski, Alison Han, Matthew J. Memoli, Jeffery K. Taubenberger, John C. Kash

Research output: Contribution to journalArticle

Abstract

In this study, we examined the relationships between anti-influenza virus serum antibody titers, clinical disease, and peripheral blood leukocyte (PBL) global gene expression during presymptomatic, acute, and convalescent illness in 83 participants infected with 2009 pandemic H1N1 virus in a human influenza challenge model. Using traditional statistical and logistic regression modeling approaches, profiles of differentially expressed genes that correlated with active viral shedding, predicted length of viral shedding, and predicted illness severity were identified. These analyses further demonstrated that challenge participants fell into three peripheral blood leukocyte gene expression phenotypes that significantly correlated with different clinical outcomes and prechallenge serum titers of antibodies specific for the viral neuraminidase, hemagglutinin head, and hemagglutinin stalk. Higher prechallenge serum antibody titers were inversely correlated with leukocyte responsiveness in participants with active disease and could mask expression of peripheral blood markers of clinical disease in some participants, including viral shedding and symptom severity. Consequently, preexisting anti-influenza antibodies may modulate PBL gene expression, and this must be taken into consideration in the development and interpretation of peripheral blood diagnostic and prognostic assays of influenza infection. IMPORTANCE Influenza A viruses are significant human pathogens that caused 83,000 deaths in the United States during 2017 to 2018, and there is need to understand the molecular correlates of illness and to identify prognostic markers of viral infection, symptom severity, and disease course. Preexisting antibodies against viral neuraminidase (NA) and hemagglutinin (HA) proteins play a critical role in lessening disease severity. We performed global gene expression profiling of peripheral blood leukocytes collected during acute and convalescent phases from a large cohort of people infected with A/H1N1pdm virus. Using statistical and machine-learning approaches, populations of genes were identified early in infection that correlated with active viral shedding, predicted length of shedding, or disease severity. Finally, these gene expression responses were differentially affected by increased levels of preexisting influenza antibodies, which could mask detection of these markers of conta-giousness and disease severity in people with active clinical disease.

Original languageEnglish (US)
Article numbere00760-19
JournalmBio
Volume10
Issue number3
DOIs
StatePublished - May 1 2019

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Hemagglutinins
Neuraminidase
Orthomyxoviridae
Leukocytes
Virus Shedding
Gene Expression
Antibodies
Human Influenza
Infection
Viral Hemagglutinins
Masks
Serum
H1N1 Subtype Influenza A Virus
Hematologic Diseases
Influenza A virus
Gene Expression Profiling
Pandemics
Virus Diseases
Genes
Anti-Idiotypic Antibodies

Keywords

  • Antibody
  • HA head antibodies
  • HA stalk antibodies
  • NA antibodies

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Differential effects of influenza virus NA, HA head, and HA stalk antibodies on peripheral blood leukocyte gene expression during human infection. / Walters, Kathie Anne; Zhu, Ruoqing; Welge, Michael; Scherler, Kelsey; Park, Jae Keun; Rahil, Zainab; Wang, Hao; Auvil, Loretta; Bushell, Colleen; Lee, Min Young; Baxter, David; Bristol, Tyler; Rosas, Luz Angela; Cervantes-Medina, Adriana; Czajkowski, Lindsay; Han, Alison; Memoli, Matthew J.; Taubenberger, Jeffery K.; Kash, John C.

In: mBio, Vol. 10, No. 3, e00760-19, 01.05.2019.

Research output: Contribution to journalArticle

Walters, KA, Zhu, R, Welge, M, Scherler, K, Park, JK, Rahil, Z, Wang, H, Auvil, L, Bushell, C, Lee, MY, Baxter, D, Bristol, T, Rosas, LA, Cervantes-Medina, A, Czajkowski, L, Han, A, Memoli, MJ, Taubenberger, JK & Kash, JC 2019, 'Differential effects of influenza virus NA, HA head, and HA stalk antibodies on peripheral blood leukocyte gene expression during human infection', mBio, vol. 10, no. 3, e00760-19. https://doi.org/10.1128/mBio.00760-19
Walters, Kathie Anne ; Zhu, Ruoqing ; Welge, Michael ; Scherler, Kelsey ; Park, Jae Keun ; Rahil, Zainab ; Wang, Hao ; Auvil, Loretta ; Bushell, Colleen ; Lee, Min Young ; Baxter, David ; Bristol, Tyler ; Rosas, Luz Angela ; Cervantes-Medina, Adriana ; Czajkowski, Lindsay ; Han, Alison ; Memoli, Matthew J. ; Taubenberger, Jeffery K. ; Kash, John C. / Differential effects of influenza virus NA, HA head, and HA stalk antibodies on peripheral blood leukocyte gene expression during human infection. In: mBio. 2019 ; Vol. 10, No. 3.
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AU - Zhu, Ruoqing

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AU - Scherler, Kelsey

AU - Park, Jae Keun

AU - Rahil, Zainab

AU - Wang, Hao

AU - Auvil, Loretta

AU - Bushell, Colleen

AU - Lee, Min Young

AU - Baxter, David

AU - Bristol, Tyler

AU - Rosas, Luz Angela

AU - Cervantes-Medina, Adriana

AU - Czajkowski, Lindsay

AU - Han, Alison

AU - Memoli, Matthew J.

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