Modelling within-host macrophage dynamics in influenza virus infection

AbstractHuman respiratory disease associated with influenza virus infection is of significant public health concern. Macrophages, as part of the front line of host innate cellular defence, have been shown to play an important role in controlling viral replication. However, fatal outcomes of infection, as evidenced in patients infected with highly pathogenic viral strains, are often associated with prompt activation and excessive accumulation of macrophages. Activated macrophages can produce a large amount of pro-inflammatory cytokines, which leads to severe symptoms and at times death. However, the mechanism for rapid activation and excessive accumulation of macrophages during infection remains unclear. It has been suggested that the phenomena may arise from complex interactions between macrophages and influenza virus. In this work, we develop a novel mathematical model to study the relationship between the level of macrophage activation and the level of viral shedding in influenza virus infection. Our model combines a dynamic model of viral infection, a dynamic model of macrophages and the essential interactions between the virus and macrophages. Our model predicts that the level of macrophage activation can be negatively correlated with the level of viral shedding when viral infectivity is sufficiently high. We further identify that temporary depletion of resting macrophages in response to viral infection is a major driver in our model for the negative relationship between macrophage activation and viral shedding, providing new insight into the mechanisms that regulate macrophage activation. Our model serves as a framework to study the complex dynamics of virus-macrophage interactions and provides a mechanistic explanation for existing experimental observations, contributing to an enhanced understanding of the role of macrophages in influenza viral infection.

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Brugada-Like Electrocardiographic Changes during Influenza Infection

Journal of International Medical Research ◽

10.1177/147323000303100313 ◽

2003 ◽

Vol 31 (3) ◽

pp. 244-246 ◽

Cited By ~ 8

Author(s):

K Kusaka ◽

J Yamakawa ◽

K Kawaura ◽

T Itoh ◽

T Takahashi ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Viral Infection ◽

Brugada Syndrome ◽

Influenza Infection ◽

Influenza Virus Infection ◽

Ecg Changes ◽

Early Repolarization ◽

Electrocardiographic Changes

We describe a 32-year-old man with electrocardiographic (ECG) changes consistent with Brugada syndrome and influenza virus infection. The ECG pattern changed after 1 week to one of early repolarization in V1 and V2. This case suggests an association between Brugada syndrome and viral infection.

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A Perfect Storm: Increased Colonization and Failure of Vaccination Leads to Severe Secondary Bacterial Infection in Influenza Virus-Infected Obese Mice

mBio ◽

10.1128/mbio.00889-17 ◽

2017 ◽

Vol 8 (5) ◽

Cited By ~ 16

Author(s):

Erik A. Karlsson ◽

Victoria A. Meliopoulos ◽

Nicholas C. van de Velde ◽

Lee-Ann van de Velde ◽

Beth Mann ◽

...

Keyword(s):

Public Health ◽

Influenza Virus ◽

Virus Infection ◽

Bacterial Infection ◽

Antibiotic Treatment ◽

Influenza Virus Infection ◽

Health Concern ◽

Obese Mice ◽

Secondary Bacterial Infection ◽

Perfect Storm

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.

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Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-κB signaling pathway

Influenza and Other Respiratory Viruses ◽

10.1111/irv.12459 ◽

2017 ◽

Vol 11 (5) ◽

pp. 457-463 ◽

Cited By ~ 19

Author(s):

Yiming Xu ◽

Ling Liu

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Signaling Pathway ◽

Lung Inflammation ◽

Macrophage Activation ◽

Influenza Virus Infection

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Defining the kinetic effects of infection with influenza virus A/PR8/34 (H1N1) on sphingosine-1-phosphate signaling in mice by targeted LC/MS

Scientific Reports ◽

10.1038/s41598-021-99765-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Divyavani Gowda ◽

Marumi Ohno ◽

Siddabasave Gowda B. Gowda ◽

Hitoshi Chiba ◽

Masashi Shingai ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza Virus Infection ◽

Health Concern ◽

Biological Responses ◽

Novel Drugs ◽

Associated Symptoms ◽

Sphingosine 1 Phosphate ◽

Kinetic Effects ◽

S1p Lyase

AbstractInfluenza remains a world-wide health concern, causing 290,000–600,000 deaths and up to 5 million cases of severe illnesses annually. Noticing the host factors that control biological responses, such as inflammatory cytokine secretion, to influenza virus infection is important for the development of novel drugs. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite and has essential biological functions in inflammation. However, the kinetic effects of influenza virus infection on physiological S1P levels and their signaling in multiple tissues remain unknown. In this study, we utilized a mouse model intranasally infected with 50 or 500 plaque forming units (PFU) of A/Puerto Rico/8/34 (H1N1; PR8) virus to investigate how S1P levels and expression of its regulating factors are affected by influenza virus infection by the liquid-chromatography/mass spectrometry and real-time PCR, respectively. The S1P level was significantly high in the plasma of mice infected with 500 PFU of the virus than that in control mice at 6 day-post-infection (dpi). Elevated gene expression of sphingosine kinase-1 (Sphk1), an S1P synthase, was observed in the liver, lung, white adipose tissue, heart, and aorta of infected mice. This could be responsible for the increased plasma S1P levels as well as the decrease in the hepatic S1P lyase (Sgpl1) gene in the infected mice. These results indicate modulation of S1P-signaling by influenza virus infection. Since S1P regulates inflammation and leukocyte migration, it must be worth trying to target this signaling to control influenza-associated symptoms.

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Influenza Virus Down-Modulates G6PD Expression and Activity to Induce Oxidative Stress and Promote Its Replication

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.804976 ◽

2022 ◽

Vol 11 ◽

Author(s):

Marta De Angelis ◽

Donatella Amatore ◽

Paola Checconi ◽

Alessandra Zevini ◽

Alessandra Fraternale ◽

...

Keyword(s):

Oxidative Stress ◽

Influenza Virus ◽

Virus Infection ◽

Viral Infection ◽

Virus Replication ◽

Influenza Virus Infection ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Host Cells ◽

Related Factor ◽

Expression And Activity

Influenza virus infection induces oxidative stress in host cells by decreasing the intracellular content of glutathione (GSH) and increasing reactive oxygen species (ROS) level. Glucose-6-phosphate dehydrogenase (G6PD) is responsible for the production of reducing equivalents of nicotinamide adenine dinucleotide phosphate (NADPH) that is used to regenerate the reduced form of GSH, thus restoring redox homeostasis. Cells deficient in G6PD display elevated levels of ROS and an increased susceptibility to viral infection, although the consequences of G6PD modulation during viral infection remain to be elucidated. In this study, we demonstrated that influenza virus infection decreases G6PD expression and activity, resulting in an increase in oxidative stress and virus replication. Moreover, the down regulation of G6PD correlated with a decrease in the expression of nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor that regulates the expression of the antioxidant response gene network. Also down-regulated in influenza virus infected cells was sirtuin 2 (SIRT2), a NADPH-dependent deacetylase involved in the regulation of G6PD activity. Acetylation of G6PD increased during influenza virus infection in a manner that was strictly dependent on SIRT2 expression. Furthermore, the use of a pharmacological activator of SIRT2 rescued GSH production and NRF2 expression, leading to decreased influenza virus replication. Overall, these data identify a novel strategy used by influenza virus to induce oxidative stress and to favor its replication in host cells. These observations furthermore suggest that manipulation of metabolic and oxidative stress pathways could define new therapeutic strategies to interfere with influenza virus infection.

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Extreme heterogeneity of influenza virus infection in single cells

eLife ◽

10.7554/elife.32303 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 105

Author(s):

Alistair B Russell ◽

Cole Trapnell ◽

Jesse D Bloom

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Viral Infection ◽

Single Cells ◽

Influenza Virus Infection ◽

Viral Gene ◽

Viral Mrnas ◽

Cellular Genes ◽

Infected Cells ◽

Cell Variation

Viral infection can dramatically alter a cell’s transcriptome. However, these changes have mostly been studied by bulk measurements on many cells. Here we use single-cell mRNA sequencing to examine the transcriptional consequences of influenza virus infection. We find extremely wide cell-to-cell variation in the productivity of viral transcription – viral transcripts comprise less than a percent of total mRNA in many infected cells, but a few cells derive over half their mRNA from virus. Some infected cells fail to express at least one viral gene, but this gene absence only partially explains variation in viral transcriptional load. Despite variation in viral load, the relative abundances of viral mRNAs are fairly consistent across infected cells. Activation of innate immune pathways is rare, but some cellular genes co-vary in abundance with the amount of viral mRNA. Overall, our results highlight the complexity of viral infection at the level of single cells.

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The protective effects of intranasal administration of IL-12 given before influenza virus infection and the negative effects of IL-12 treatment given after viral infection

Journal of Medical Virology ◽

10.1002/jmv.24494 ◽

2016 ◽

Vol 88 (9) ◽

pp. 1487-1496 ◽

Cited By ~ 3

Author(s):

Hiroki Ishikawa ◽

Satoshi Ino ◽

Hiraku Sasaki ◽

Toshie Fukui ◽

Chikara Kohda ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Viral Infection ◽

Intranasal Administration ◽

Influenza Virus Infection ◽

Protective Effects ◽

Negative Effects

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Macaque Proteome Response to Highly Pathogenic Avian Influenza and 1918 Reassortant Influenza Virus Infections

Journal of Virology ◽

10.1128/jvi.01129-10 ◽

2010 ◽

Vol 84 (22) ◽

pp. 12058-12068 ◽

Cited By ~ 32

Author(s):

Joseph N. Brown ◽

Robert E. Palermo ◽

Carole R. Baskin ◽

Marina Gritsenko ◽

Patrick J. Sabourin ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Avian Influenza ◽

Viral Infection ◽

Highly Pathogenic Avian Influenza ◽

Influenza Virus Infection ◽

Delayed Response ◽

Protein Database ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza

ABSTRACT The host proteome response and molecular mechanisms that drive disease in vivo during infection by a human isolate of the highly pathogenic avian influenza virus (HPAI) and 1918 pandemic influenza virus remain poorly understood. This study presents a comprehensive characterization of the proteome response in cynomolgus macaque (Macaca fascicularis) lung tissue over 7 days of infection with HPAI (the most virulent), a reassortant virus containing 1918 hemagglutinin and neuraminidase surface proteins (intermediate virulence), or a human seasonal strain (least virulent). A high-sensitivity two-dimensional liquid chromatography-tandem mass spectroscopy strategy and functional network analysis were implemented to gain insight into response pathways activated in macaques during influenza virus infection. A macaque protein database was assembled and used in the identification of 35,239 unique peptide sequences corresponding to approximately 4,259 proteins. Quantitative analysis identified an increase in expression of 400 proteins during viral infection. The abundance levels of a subset of these 400 proteins produced strong correlations with disease progression observed in the macaques, distinguishing a “core” response to viral infection from a “high” response specific to severe disease. Proteome expression profiles revealed distinct temporal response kinetics between viral strains, with HPAI inducing the most rapid response. While proteins involved in the immune response, metabolism, and transport were increased rapidly in the lung by HPAI, the other viruses produced a delayed response, characterized by an increase in proteins involved in oxidative phosphorylation, RNA processing, and translation. Proteomic results were integrated with previous genomic and pathological analysis to characterize the dynamic nature of the influenza virus infection process.

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The Importance of Vaccinating Children and Pregnant Women against Influenza Virus Infection

Pathogens ◽

10.3390/pathogens8040265 ◽

2019 ◽

Vol 8 (4) ◽

pp. 265 ◽

Cited By ~ 4

Author(s):

Ravi S Misra ◽

Jennifer L Nayak

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Viral Infection ◽

Pregnant Women ◽

Influenza Virus Infection ◽

Infection Rates ◽

Public Health Burden ◽

Vaccination Rates ◽

The Public ◽

Lower Infection

Influenza virus infection is responsible for significant morbidity and mortality in the pediatric and pregnant women populations, with deaths frequently caused by severe influenza-associated lower respiratory tract infection and acute respiratory distress syndrome (ARDS). An appropriate immune response requires controlling the viral infection through activation of antiviral defenses, which involves cells of the lung and immune system. High levels of viral infection or high levels of inflammation in the lower airways can contribute to ARDS. Pregnant women and young children, especially those born prematurely, may develop serious complications if infected with influenza virus. Vaccination against influenza will lead to lower infection rates and fewer complications, even if the vaccine is poorly matched to circulating viral strains, with maternal vaccination offering infants protection via antibody transmission through the placenta and breast milk. Despite the health benefits of the influenza vaccine, vaccination rates around the world remain well below targets. Trust in the use of vaccines among the public must be restored in order to increase vaccination rates and decrease the public health burden of influenza.

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