The immunopathology of SARS-Cov-2 co-infection with influenza virus

ACHAIKI IATRIKI | 2022; 41(2): 57–60

Editorial

Evanthia Tourkochristou1, Markos Marangos2


1Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
2Division of Infectious Diseases, Department of Internal Medicine, University Hospital of Patras, Patras, Greece

Received: 25 May 2022; Accepted: 18 May 2022

Corresponding author: Evanthia Tourkochristou, MSc, PhD Candidate, Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece, Tel.: +30 2610 969148, E-mail: evanthiatourkohristou@gmail.com, ORCID: 0000-0003-1586-6854

Key words: SARS-Cov-2, influenza, viruses, co-infection, immunopathology

 


INTRODUCTION

The emergence of Covid-19 in the influenza season has posed a new challenge to the healthcare system, regarding the clinical impact of a potent co-infection on disease severity and health-service demand. Covid-19 and seasonal influenza can be detrimental for the same high-risk groups, including persons of older age, persons with chronic co-morbidities and residents of long-term care facilities [1,2]. Pulmonary immunopathology is the leading cause of mortality in both SARS-Cov-2 and influenza infections, as the host’s response to viral invasion could be deleterious and contribute to severe disease phenotypes. There is experimental evidence, reporting that pre-infection with influenza virus significantly promotes SARS-CoV-2 virus entry and infectivity in cells and animals [3]. However, investigation of the impact of SARS-Cov-2 and influenza co-existence on clinical outcomes, immunopathology and tissue repair following viral lower respiratory tract infection is still ongoing. The understanding of the mechanisms underlying the pathologic interaction between SARS-Cov-2 and influenza virus is of high clinical significance to inform treatment and control strategies for the effective management of all sets of patients.

An overview of SARS-Cov-2 and influenza viruses

Influenza viruses are enveloped segmented, single-stranded, negative sense RNA viruses of the Orthomyxoviridae family, which includes four genera, influenza virus A–D (IAV, IBV, ICV and IDV) [4,5]. Coronaviruses are enveloped single-stranded non-segmented RNA viruses of the Coronaviridae family, which are classified into four genera (alphacoronaviruses, betacoronaviruses, gammacoronaviruses and deltacoronaviruses) [6]. Respiratory epithelial cells (types I and II alveolar epithelial cells) are the primary targets of both influenza and SARS-Cov-2 viruses, which use specific surface receptors to enter host cells. Considering that these two viruses can infect the same types of respiratory cells, SARS-Cov-2 co-infection with influenza viruses could have a negative impact on disease course and clinical outcomes. The haemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza viruses bind to epithelial cell surface sialosaccharides (SA) and the spike protein of SARS-Cov-2 uses the transmembrane angiotensin converting enzyme 2 (ACE2) receptor for epithelial cell entry. HA and spike protein are processed by specific host proteases to initiate virus-host cell fusion. Other types of epithelial cells, including the intestinal epithelial cells, endothelial cells and renal parenchymal cells are also infected by SARS-Cov-2. Thus, SARS-Cov-2 shows extensive extrapulmonary complications compared to influenza viruses, which affect mainly the upper and lower respiratory tract [7]. Years of prior influenza exposure and national implementation of influenza vaccination policies that contribute to a significant level of population immunity seem to be responsible for a lower influenza R0 (1.28) compared to SARS-Cov-2 R0 (3.6-6.1), as pre-existing immunity to SARS-Cov-2 is lacking [8,9]. Elucidation of viral dynamics and immune-encountering through time, could provide useful guidance to the investigation of the disease course and effective management of SARS-Cov-2 co-infection with influenza viruses.

Host background immunity of SARS-Cov-2 co-infection with influenza viruses and pathophysiology

Common immune responses initiate after invasion of both SARS-Cov-2 and influenza viruses into the host cells. Respiratory epithelial cells, after encountering the SARS-Cov-2 and influenza viruses produce antiviral and chemotactic molecules, which recruit innate effector cells, including natural killer cells, monocytes, dendritic cells (DCs) and neutrophils. Pathogen recognition receptors (PRRs) present on innate immune cells, recognize the viral particles by binding to viral conserved components called pathogen associated molecular patterns (PAMPs), initiating a signaling cascade that results in the activation of transcription factors (NF-Κβ, IRFs) and induction of gene expression of pro-inflammatory cytokines and anti-viral peptides. Production of pro-inflammatory cytokines by host cells is associated with infection with IAV or SARS-CoV-2 [10]. Elevated inflammatory cytokines may be involved in the induction of endothelial leak and contribute to pathogenesis. A systemic inflammatory response with the excessive activation of immune cells and proinflammatory mediators such as IFN-α, IL-1β, and IL-6, that lead to lung injury and respiratory failure characterizes the COVID-19- associated severe cases [11]. High levels of cytokines have been observed in the lung of SARS-Cov-2 and influenza infected patients and side effects could be attributed to abnormal levels of specific cytokines [12]. SARS-Cov-2 and influenza virus infection of the alveolar capillary endothelium could contribute to pulmonary edema and venous thromboembolism, probably through cytokine-induced endothelial activation or cell death. Activated neutrophils in the respiratory epithelium release neutrophil extracellular traps (NETs). NETs have been associated with tissue damage, hypercoagulability, and thrombosis, as they directly cause endothelial and epithelial cell death, promote thrombosis by acting as a scaffold and activating platelets, recruit pro-coagulation factors, bind von Willebrand factor (vWF) and fibrin to recruit platelets, and enhance production of inflammatory cytokines by immune cells [13]. Enhanced adhesion and activation of platelets during both influenza and SARS-CoV-2 infection could amplify the inflammatory response, resulting in further endothelial activation, vascular leak and disseminated intravascular coagulation. Activated platelets can release inflammatory cytokines and chemokines, which induce endothelial expression of cell adhesion molecules such as ICAM-1, VCAM-1, E-Selectin, and P-Selectin and proinflammatory cytokines and chemokines such as IL-6, IL-8 and MCP-1 (CCL2). Many inflammatory mediators such as vascular endothelial growth factor (VEGF) can induce the phosphorylation and endocytosis of major protein of endothelial adherents junctions, thereby disrupting endothelial barrier function [13] (Figure 1).

Figure 1. Host immunity of SARS-Cov-2 co-infection with influenza viruses and pathophysiology. Haemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza viruses bind to epithelial cell surface sialosaccharides (SA) and spike (S) protein of SARS-Cov-2 relies on transmembrane angiotensin converting enzyme 2 (ACE2) receptor for epithelial cell entry. Respiratory epithelial cells (alveolar type I and alveolar type II cells), after encountering with the SARS-Cov-2 and influenza viruses produce antiviral and chemotactic molecules, which recruit innate effector cells, including natural killer cells, monocytes, dendritic cells (DCs) and neutrophils. Cytokine-induced endothelial activation or cell death could contribute to pulmonary edema and venous thromboembolism. Activated neutrophils in the respiratory epithelium release neutrophil extracellular traps (NETs), leading probably to tissue damage, hypercoagulability, and thrombosis, as they directly cause endothelial and epithelial cell death, promote thrombosis by acting as a scaffold and activating platelets and recruit pro-coagulation factors. Activated platelets can release inflammatory cytokines and chemokines, which induce endothelial expression of cell adhesion molecules such as ICAM-1, P-Selectin. Many inflammatory mediators such as vascular endothelial growth factor (VEGF) can disrupt endothelial barrier function. T helper cells (CD4+ T cells, Th) are activated by DCs, express antiviral cytokines (IFN-γ, TNF, IL-2) that activate alveolar macrophages to phagocyte viral particles and CD4+ T cells also produce IL-4 and IL-13 to promote B cell responses and antibody production. Cytotoxic T lymphocytes (CTLs) produce cytokines and effector molecules to restrict viral replication and kill virus-infected cells. In mild Covid-19 Th1 responses and activated macrophages, CTLs and B cells play major role in viral clearance. In influenza infection, TNF-α and IFN-γ cytokines induce antiviral responses in the lung and IL-1 increases IgM antibody responses. Th2 cells by secreting IL4, IL-5 and IL-13 suppress antiviral immune responses, contribute to elevating eosinophil infiltration in the lungs, resulting in changes of the contractile apparatus of airway smooth muscle and mucus production.

Initiation of adaptive immune responses is crucial for an effective coordinated immune response against the virus and achievement of immune homeostasis. Adaptive immunity begins when naïve and memory T lymphocytes recognize SARS-Cov-2 and influenza viral antigens presented by major histocompatibility complex (MHC) proteins on the surface of DCs, migrated from lungs to T-cell zone of the draining lymph nodes. In particular, T helper cells (CD4+ T cells, Th) are activated through binding to viral peptides on MHC-II molecules and differentiate into Th subpopulations with separate functions. Th1 cells express antiviral cytokines, such as IFN-γ, TNF, and IL-2 and activate alveolar macrophages to phagocyte viral particles, whereas Th2 cells produce IL-4 and IL-13 to promote B cell responses and antibody production. T regulatory cells play a major role in modulating immune responses, establishing the immune homeostasis. CD8+ T cells are also activated by DCs and differentiate into cytotoxic T lymphocytes (CTLs), which produce cytokines and effector molecules to restrict viral replication and kill virus-infected cells [10,14]. In severe Covid-19 disease secretion of IL-4, IL-5, IL-13, and IL-10 cytokines by Th2 cells delays clearance of the virus via inhibition of anti-viral responses. In mild Covid-19 Th1 responses and activated macrophages, CTLs and B cells play major role in viral clearance. TNF-α and IFN-γ induce antiviral responses directly through their receptors on the epithelial surfaces of the lung [12]. In influenza infection, tissue damage, pathogen removal and the inflammatory response processing the acute lung injury infection are under the effect of T helper polarization. TNF-α and IFN-γ cytokines induce antiviral responses in the lung and IL-1 increases IgM antibody responses. Th2 cells by secreting IL-4, IL-5 and IL-13 suppress antiviral immune responses, activate natural killer T cells, eosinophil, macrophage, and mast cells and contribute to elevating eosinophil infiltration in the lungs, resulting in changes of the contractile apparatus of airway smooth muscle, macrophage polarization, following mucus production, and elevating aryl hydrocarbon receptor (AHR) and goblet cell metaplasia [12] (Figure 1).

Although SARS-Cov-2 and influenza viruses induce common immune responses, understanding of their correlation is still ongoing. A possible impact of influenza specific T cell immunity on immune responses to SARS-CoV-2 has been suggested. Influenza HIN1 antigen specific CD4+ T cells have been found in 92% COVID+ and 76% COVID- subjects and exhibited a strong direct correlation with SARS-CoV-2 specific CD4+ T cells [15]. A potent interaction between the immune components of both infections should be further investigated to provide useful information regarding the dynamics of SARS-Cov-2 and influenza virus co-existence. In literature there are two sides of the coin, about how aggravating a SARS-Cov-2 co-infection with influenza virus could be for disease course. SARS-Cov-2 co-infection with IAV has been associated with a prolonged primary virus infection period, increased immune cell infiltration and inflammatory cytokine levels in bronchoalveolar lavage fluid which led to severe pneumonia and lung damage compared to SARS-Cov-2 and IAV monoinfections. Moreover, severe lymphopenia in peripheral blood, resulting in reduced total IgG, neutralizing antibody titers, and CD4+ T cell responses against each virus has been linked to co-infection [16]. Similar patterns of symptoms and clinical outcomes have been observed among patients with SARS‐CoV‐2 infection only and patients with SARS‐CoV‐2/IFV‐A co‐infection in a retrospective cohort study. An increased expression of serum cytokines (interleukin‐2R [IL‐2R], IL‐6, IL‐8, and tumor necrosis factor‐α) and cardiac troponin I, and higher incidence of lymphadenopathy were observed in patients with SARS‐CoV‐2 infection only. Male patients and patients aged less than 60 years in the SARS‐CoV‐2 infection group also had significantly higher computed tomography scores than patients in the co‐infection group, indicating that co‐infection with IFV‐A had no effect on disease outcome but alleviated inflammation in certain populations of COVID‐19 patients [17]. Further observational studies with systematic analysis of clinical outcomes in co-infected patients compared with those mono-infected are needed to elucidate whether SARS-Cov-2 and influenza co-existence contributes to increased disease severity, regarding mortality, incidence of shock, being admitted to an intensive care unit (ICU) or requiring ventilatory support. Knowledge of pathogenic interactions between SARS-CoV-2 and influenza virus is limited so far. A better understanding of the host immune responses and immunopathological features that distinguish the two infections will provide useful guidance for the design of effective therapeutic approaches and vaccine development.

Conflict of interest disclosure

None to declare

Declaration of funding sources

None to declare

Authors’ contributions

ET and MM designed and coordinated the study, performed the literature search and analysis, and wrote the manuscript. Both authors approved the submitted version of the manuscript.

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