Severe COVID-19: what have we learned with the immunopathogenesis?

Abstract

The COVID-19 outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global major concern. In this review, we addressed a theoretical model on immunopathogenesis associated with severe COVID-19, based on the current literature of SARS-CoV-2 and other epidemic pathogenic coronaviruses, such as SARS and MERS. Several studies have suggested that immune dysregulation and hyperinflammatory response induced by SARS-CoV-2 are more involved in disease severity than the virus itself.

Immune dysregulation due to COVID-19 is characterized by delayed and impaired interferon response, lymphocyte exhaustion and cytokine storm that ultimately lead to diffuse lung tissue damage and posterior thrombotic phenomena.

Considering there is a lack of clinical evidence provided by randomized clinical trials, the knowledge about SARS-CoV-2 disease pathogenesis and immune response is a cornerstone to develop rationale-based clinical therapeutic strategies. In this narrative review, the authors aimed to describe the immunopathogenesis of severe forms of COVID-19.

Background

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA-enveloped virus, is the causative agent of coronavirus disease 2019 (COVID-19), being first identified in Wuhan, China, in December 2019. Previously, other epidemic coronavirus such as severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and the middle-east respiratory syndrome coronavirus (MERS-CoV) in 2012, had serious impact on human health and warned the world about the possible reemergence of new pathogenic strains [1]. Despite being a new virus, several common morpho-functional characteristics have been reported between SARS-CoV and the SARS-CoV-2, including the interaction of the viral spike (S) glycoprotein with the human angiotensin converting enzyme 2 (ACE2). These similarities may help understanding some pathophysiological mechanisms and pointing out possible therapeutic targets.

The first step for SARS-CoV-2 entry into the host cell is the interaction between the S glycoprotein and ACE2 on cell surface. Since the latter acts as a viral receptor, the virus will only infect ACE2 expressing cells, notably type II pneumocytes. These cells represent 83% of the ACE2-expressing cells in humans, but cells from other tissues and organs, such as heart, kidney, intestine and endothelium, can also express this receptor [2]. A host type 2 transmembrane serine protease, TMPRSS2, facilitates virus entry by priming S glycoprotein. TMPRSS2 entails S protein in subunits S1/S2 and S2´, allowing viral and cellular membrane fusion driven by S2 subunit [3]. Once inside the cell viral positive sense single strand RNA is translated into polyproteins that will form the replicase-transcriptase complex. This complex function as a viral factory producing new viral RNA and viral proteins for viral function and assembly [4]. Considering these particularities, the infection first begins on upper respiratory tract mucosa and then reaches the lungs. The primary tissue damage is related to the direct viral cytopathic effects. At this stage, the virus has the potential to evade the immune system, where an inadequate innate immune response can occur, depending on the viral load and other unknown genetic factors. Subsequently, tissue damage is induced by additional mechanisms derived from a dysregulated adaptive immune response [5].

Although most of COVID-19 cases have a mild clinical course, up to 14% can evolve to a severe form, with respiratory rate ≥ 30/min, hypoxemia with pulse oxygen saturation ≤ 93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300 and/or pulmonary infiltrates involving more than 50% of lung parenchyma within 24 to 48 h. Up to 5% of the cases can be critical, evolving with respiratory failure, septic shock and/or multiple organ dysfunction, presumably driven by a cytokine storm [6]. Host characteristics, including aging (immunosenescence) and comorbidities (hypertension, diabetes mellitus, lung and heart diseases) may influence the course of the disease [7]. The false paradox between inflammation and immunodeficiency is highlighted by the severe form of COVID-19. Thus, severe pneumonia caused by SARS-CoV-2 is marked by immune system dysfunction and hyperinflammation leading to acute respiratory distress syndrome (ARDS), macrophage activation, hypercytokinemia and coagulopathy [8].

Herein, we aim to review the factors related to the dysregulated immune response against the SARS-CoV-2, along with its relation with severe forms of COVID-19, namely ARDS and cytokine storm (CS).

For More Information: https://advancesinrheumatology.biomedcentral.com/articles/10.1186/s42358-020-00151-7

Pathophysiology of COVID-19:

Mechanisms Underlying Disease Severity and Progression

Authors: Mary Kathryn Bohn,1,2, Alexandra Hall,1 Lusia Sepiashvili,1,2, Benjamin Jung,1,2 Shannon, Steele,1 and Khosrow Adeli1,2,3

The global epidemiology of coronavirus disease 2019 (COVID-19) suggests a wide spectrum of clinical severity, ranging from asymptomatic to fatal. Although the clinical and laboratory characteristics of COVID-19 patients have been well characterized, the pathophysiological mechanisms underlying disease severity and progression remain unclear. This review highlights key mechanisms that have been proposed to contribute to COVID-19 progression from viral entry to multisystem organ failure, as well as the central role of the immune response in successful viral clearance or progression to death.

Introduction

Coronavirus disease 2019 (COVID-19) is caused by a novel beta-coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). As of June 15, 2020, the number of global confirmed cases has surpassed 8 million, with over 400,000 reported mortalities. The unparalleled pathogenicity and global impact of this pandemic has rapidly engaged the scientific community in urgently needed research. Preliminary reports from the Chinese Center for Disease Control and Prevention have estimated that the large majority of confirmed SARS-CoV-2 cases are mild (81%), with ~14% progressing to severe pneumonia and 5% developing acute respiratory distress syndrome (ARDS), sepsis, and/or multisystem organ failure (MOF) (144). Although more data is urgently needed to elucidate the global epidemiology of COVID-19 (80), a wide spectrum of clinical severity is evident, with most patients able to mount a sufficient and appropriate immune response, ultimately leading to viral clearance and case resolution. However, a significant subset of patients present with severe clinical manifestations, requiring life-supporting treatment (51). The pathophysiological mechanisms behind key events in the progression from mild to severe disease remain unclear, warranting further investigation to inform therapeutic decisions. Here, we review the current literature and summarize key proposed mechanisms of COVID-19 pathophysiological progression (FIGURE 1). Key Pathophysiological Mechanisms: Our Current Understanding Viral Invasion The first step in COVID-19 pathogenesis is viral invasion via its target host cell receptors. SARSCoV-2 viral entry has been described in detail elsewhere (138). In brief, SARS-CoV-2 consists of four main structural glycoproteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N). The M, E, and N proteins are critical for viral particle assembly and release, whereas the S protein is responsible for viral binding and entry into host cells (33, 76, 89, 143, 148). Similar to SARS-CoV, several researchers have identified human angiotensin converting enzyme 2 (ACE2) as an entry receptor for SARS-CoV-2 (75, 99, 148, 156). SARSCoV-2 is mostly transmissible through large respiratory droplets, directly infecting cells of the upper and lower respiratory tract, especially nasal ciliated and alveolar epithelial cells (161). In addition to the lungs, ACE2 is also expressed in various other human tissues, such as the small intestine, kidneys, heart, thyroid, testis, and adipose tissue, indicating the virus may directly infect cells of other organ systems when viremia is present (77). Interestingly, although the S proteins of SARS-CoV-2 and SARSCoV share 72% homology in amino acid sequences, SARS-CoV-2 has been reported to have a higher affinity for the ACE2 receptor (18, 21, 143). Following host cell binding, viral and cell membranes fuse, enabling the virus to enter into the cell (89). For many coronaviruses, including SARS-CoV, host cell binding alone is insufficient to facilitate membrane fusion, requiring S-protein priming or cleavage by host cell proteases or transmembrane serine proteases (9, 10, 90, 94, 108). Indeed, Hoffman and colleagues demonstrated that S-protein priming by transmembrane serine protease 2 (TMPRSS2), which may be substituted by cathepsin B/L, is required to facilitate SARS-CoV-2 entry into host cells (58). In addition, unlike other coronaviruses, SARS-CoV-2 has been reported to possess a furin-like cleavage site in the S-protein domain, located between the S1 and S2 subunits (31, 138). Furin-like proteases are ubiquitously expressed, albeit at low levels, indicating that S-protein priming at this cleavage site may contribute to the widened cell tropism and enhanced transmissibility of SARS-CoV-2 (123). However, whether furin-like protease-mediated cleavage is required for SARS-CoV-2 host entry has yet to be determined. Blocking or inhibiting these processing enzymes may serve as a potential antiviral target (130). Interestingly, SARS-CoV-2 has developed a unique S1/S2 cleavage site in its S protein, characterized by a four-amino acid insertion, which seems to be absent in all other coronaviruses (4). This molecular mimicry has been identified as an efficient evolutionary adaptation that some viruses have acquired for exploiting the host cellular machinery. Once the nucleocapsid is deposited into the cytoplasm of the host cell, the RNA genome is replicated and translated into structural and accessory proteins. Vesicles containing the newly formed viral particles are then transported to and fuse with the plasma membrane, releasing them to infect other host cells in the same fashion (33, 89, 105). Although much progress has been made in our understanding of the mechanisms underlying SARS-CoV-2 invasion, additional research is needed to delineate exactly how cleavage of the S proteins by TMPRSS2 confers viral particle entry as well as how S-protein cleavage by membrane proteases contributes to viral penetration.

For More Information: https://journals.physiology.org/doi/pdf/10.1152/physiol.00019.2020

Age-dependent appearance of SARS-CoV-2 entry sites in mouse chemosensory systems reflects COVID-19 anosmia-ageusia symptoms

Authors: Julien Brechbühl,Ana Catarina Lopes,Dean Wood,Sofiane Bouteiller,Aurélie de Vallière,Chantal Verdumo, and Marie-Christine Broillet

Abstract

COVID-19 pandemic has given rise to a collective scientific effort to study its viral causing agent SARS-CoV-2. Research is focusing in particular on its infection mechanisms and on the associated-disease symptoms. Interestingly, this environmental pathogen directly affects the human chemosensory systems leading to anosmia and ageusia. Evidence for the presence of the cellular entry sites of the virus, the ACE2/TMPRSS2 proteins, has been reported in non-chemosensory cells in the rodent’s nose and mouth, missing a direct correlation between the symptoms reported in patients and the observed direct viral infection in human sensory cells. Here, mapping the gene and protein expression of ACE2/TMPRSS2 in the mouse olfactory and gustatory cells, we precisely identify the virus target cells to be of basal and sensory origin and reveal the age-dependent appearance of viral entry-sites. Our results propose an alternative interpretation of the human viral-induced sensory symptoms and give investigative perspectives on animal models.

Introduction

The Corona Virus Disease 2019 (COVID-19) has federated worldwide scientific efforts for understanding the viral epidemiological mechanisms of the coronavirus 2 (SARS-CoV-2) that causes this severe acute respiratory syndrome. In humans, the viral syndrome is characterized by an increased mortality rate in aged and/or comorbidity patients associated with the upper respiratory infection symptoms, such as severe respiratory distress13. In addition to its major impact, COVID-19 is associated by its direct alteration of human olfaction and gustation, in absence of substantial nasal inflammation or coryzal signs, resulting to anosmia and ageusia in up to 77% of the patients47. While these sensory symptoms are well established and intensely affect everyday behaviors8,9, the precise related mechanisms remain elusive10.

The target cells of the virus share a molecular signature: the concomitant cellular expression of the angiotensin-converting enzyme 2 (ACE2) and of its facilitating transmembrane serine protease 2 (TMPRSS2), which plays a crucial role for the interaction of viral spike proteins with the host cell1113. Paradoxically, these entry sites seem to be lacking in sensory cells1418, while a direct SARS-CoV-2 contamination has been observed both in humans and rodents19,20, requesting further investigations to explain the sensory-associated symptoms2124. Therefore, the characterization of the animal model is necessary prior to its use to understand the causality underling the viral-induced sensory symptoms.

The use of mice is indeed limited for epidemiological studies due to their absence of hands, which, with aerosols, are the foremost passages of interindividual viral transmission25, as well as their published lack of SARS-CoV-2 ACE2-spike protein affinity26,27. Nevertheless, the ease of production of genetically modified mice and their scientific availability, as well as their well-studied and specialized chemosensory systems2830, make them a valuable ally for the development of potential prophylactic and protective treatments related to these sensory symptoms.

Thus, we aimed here at characterizing the potential viral entry sites across mouse sensory systems. We found SARS-CoV-2 entry cells to be of different origins depending on the sensory systems. In summary, the virus could target cells involved in tissue regulation such as the supporting cells of the olfactory receptor neurons and the regenerative basal cells but also, specifically, the chemosensory cells of both gustatory and olfactory systems. We finally revealed that the emergence of viral entry sites in sensory and basal cells only occurs with age, which could explain both, the observed COVID-19 long-lasting effects and the age-dependent sensory-symptomatology in human.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282876/