A potential role for integrins in host cell entry by SARS-CoV-2

Sigrist, Christian J. A.; Bridge, Alan; Mercier, Philippe Le

doi:10.1016/j.antiviral.2020.104759

Cited by 296 publications

(317 citation statements)

References 25 publications

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“…It should be remembered here that the ON and vomeronasal nerve serve as a scaffold to guide gonadotropin-releasing hormone (GnRH) neurons from the nose to the hypothalamus during development (47), a process for which Neuropilin-1 is essential (48,49), and that a continuum of GnRH neurons persists in adulthood, directly connecting olfactory areas to the hypothalamus. Additionally, the theoretical ability of the S-protein to bind to alternative receptors (50) or be cleaved by other proteases (51) makes it possible that molecules other than ACE2 and TMPRSS2 also mediate viral entry, expanding the range of susceptible cells, and the putative trans-activation of the virus could obviate the need for the coexpression of the two molecules on the same host cell (52).…”

Section: Discussionmentioning

confidence: 99%

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

Nampoothiri

Sauvé

Ternier

et al. 2020

Preprint

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Most patients with COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), display neurological symptoms, and respiratory failure in certain cases could be of extrapulmonary origin. Hypothalamic neural circuits play key roles in sex differences, diabetes, hypertension, obesity and aging, all risk factors for severe COVID-19, besides being connected to olfactory/gustative and brainstem cardiorespiratory centers. Here, human brain gene-expression analyses and immunohistochemistry reveal that the hypothalamus and associated regions express angiotensin-converting enzyme 2 and transmembrane proteinase, serine 2, which mediate SARS-CoV-2 cellular entry, in correlation with genes or pathways involved in physiological functions or viral pathogenesis. A post-mortem patient brain shows viral invasion and replication in both the olfactory bulb and the hypothalamus, while animal studies indicate that sex hormones and metabolic diseases influence this susceptibility. Main textSARS-CoV-2 infection is increasingly associated with a wide range of neurological symptomsheadaches, dizziness, nausea, loss of consciousness, seizures, encephalitis etc., as well as anosmia or ageusia -in the majority of patients (1,2). Additionally, many COVID-19 patients with severe disease do not respond well to artificial ventilation or display "silent hypoxia" (3), suggesting an extrapulmonary component to respiratory dysfunction, and cardiorespiratory function and fluid homeostasis are themselves subject to central nervous system (CNS) control. However, despite emerging reports of the post-mortem detection of the virus in the cerebrospinal fluid (CSF) (see for example (4)) or brain parenchyma of patients (5), little is known about how and under what circumstances SARS-CoV-2 infects the brain.While the possibility of CNS infection has been largely underestimated due to the common view that angiotensin converting enzyme 2 (ACE2), the only confirmed cellular receptor for SARS-CoV-2 so far (6), is absent or expressed only at very low levels in the brain (7,8), and that too exclusively in vascular cells (He et al., bioRxiv 2020; doi: https://doi.org/10.1101.088500) the majority of these studies have focused on the cerebral cortex, ignoring the fact that other regions such as the hypothalamus, are rich in ACE2 (9). Intriguingly, most major risk factors for severe COVID-19 (male sex, age, obesity, hypertension, diabetes); reviewed by (10,11); could be mediated by normal or dysfunctional hypothalamic neural networks that regulate a variety of physiological processes: sexual differentiation and gonadal hormone production, energy homeostasis, fluid homeostasis/osmoregulation and even ageing (12)(13)(14). The hypothalamus is also directly linked to other parts of the CNS involved in functions affected in COVID-19 patients, including brainstem nuclei that control fluid homeostasis, cardiac function and respiration, as well as regions implicated in the perception or integration of odor and taste (12,(14)(15)(16)(17)(18).Here, we inves...

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Section: Discussionmentioning

confidence: 99%

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

Nampoothiri

Sauvé

Ternier

et al. 2020

Preprint

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“…The coronavirus disease 2019 (COVID-19) which started in Wuhan, China, and affected most of the country, is spreading rapidly throughout the world in spite of the concerted efforts from the governments and World Health Organization (WHO) to contain it. The virus spreads 1000 times faster than the other viral strains inside the body and causes various kind of illnesses [1]. Korea is also adversely affected by COVID-19 due to its geographical proximity to China.…”

mentioning

confidence: 99%

COVID-19, A Clinical Syndrome Manifesting as Hypersensitivity Pneumonitis

Song

Shin

2020

Infect Chemother

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“…Integrins were reported important for the entry of SARS-CoV into the host cells [65], so it was speculated similar phenomenon might also be present in SARS-CoV-2. This idea is further intensified after the study by Sigrist et al [63], who suggested the presence of an integrin-binding RGD motif in the spike of SARS-CoV-2. Surprisingly, upon the gene expression comparison between the different SARS-CoV-2 infected cells, we observed several folds upregulated expressions of genes related to the integrin signaling pathway in lung cells.…”

Section: Discussionmentioning

confidence: 99%

“…Several previous reports suggested an important aspect of integrins in SARS-CoV-2 pathogenesis, therefore, we sought to find out the expression profiles of integrin related genes in different COVID-19 infection models at sample level [63,64]. RGD motif of the spike protein of SARS-CoV-2 can bind the integrins and this motif is placed near to the ACE2receptor binding motif [63].…”

Section: Genes Related To Integrins and Integrin Signaling Pathway Armentioning

confidence: 99%

Host transcriptional responses and SARS-CoV-2 isolates from the nasopharyngeal samples of Bangladeshi COVID-19 patients

Islam

Khan

Ahmed

et al. 2020

Preprint

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As the COVID-19 pandemic progresses, fatality and cases of new infections are also increasing at an alarming rate. SARS-CoV-2 follows a highly variable course and it is becoming more evident that individual’s immune system has a decisive influence on the progression of the disease. However, the detailed underlying molecular mechanisms of the SARS-CoV-2 mediate disease pathogenesis are largely unknown. Only a few host transcriptional responses in COVID-19 have been reported so far from the Western world, but no such data has been generated from the South-Asian region yet to correlate the conjectured lower fatality around this part of the globe. In this context, we aimed to perform the transcriptomic profiling of the COVID-19 patients from Bangladesh along with the reporting of the SARS-CoV-2 isolates from these patients. Moreover, we performed a comparative analysis to demonstrate how differently the various SARS-CoV-2 infection systems are responding to the viral pathogen. We detected a unique missense mutation at 10329 position of ORF1ab gene, annotated to 3C like proteinase, which is found in 75% of our analyzed isolates; but is very rare globally. Upon the functional enrichment analyses of differentially modulated genes, we detected a similar host induced response reported earlier; this response was mainly mediated by the innate immune system, interferon stimulation, and upregulated cytokine expression etc. in the Bangladeshi patients. Surprisingly, we did not perceive the induction of apoptotic signaling, phagosome formation, antigen presentation and production, hypoxia response within these nasopharyngeal samples. Furthermore, while comparing with the other SARS-CoV-2 infection systems, we spotted that lung cells trigger the more versatile immune and cytokine signaling which was several folds higher compared to our reported nasopharyngeal samples. We also observed that lung cells did not express ACE2 in a very high amount as suspected, however, the nasopharyngeal cells are found overexpressing ACE2. But the amount of DPP4 expression within the nasal samples was significantly lower compared to the other cell types. Surprisingly, we observed that lung cells express a very high amount of integrins compared to the nasopharyngeal samples, which might suggest the putative reasons for an increased amount of viral infections in the lungs. From the network analysis, we got clues on the probable viral modulation for the overexpression of these integrins. Our data will provide valuable insights in developing potential studies to elucidate the roles of ethnicity effect on the viral pathogenesis, and incorporation of further data will enrich the search of an effective therapeutics.

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A potential role for integrins in host cell entry by SARS-CoV-2

Cited by 296 publications

References 25 publications

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis

COVID-19, A Clinical Syndrome Manifesting as Hypersensitivity Pneumonitis

Host transcriptional responses and SARS-CoV-2 isolates from the nasopharyngeal samples of Bangladeshi COVID-19 patients

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