More than two and a half years have already passed since the first case of COVID-19 was officially reported (December 2019), as well as more than two years since the WHO declared the current pandemic (March 2020). During these months, the advances on the knowledge of the COVID-19 and SARS-CoV-2, the coronavirus responsible of the infection, have been very significant. However, there are still some weak points on that knowledge, being the origin of SARS-CoV-2 one of the most notorious. One year ago, I published a review focused on what we knew and what we need to know about the origin of that coronavirus, a key point for the prevention of potential future pandemics of a similar nature. The analysis of the available publications until July 2021 did not allow drawing definitive conclusions on the origin of SARS-CoV-2. Given the great importance of that issue, the present review was aimed at updating the scientific information on that origin. Unfortunately, there have not been significant advances on that topic, remaining basically the same two hypotheses on it. One of them is the zoonotic origin of SARS-CoV-2, while the second one is the possible leak of this coronavirus from a laboratory. Most recent papers do not include observational or experimental studies, being discussions and positions on these two main hypotheses. Based on the information here reviewed, there is not yet a definitive and well demonstrated conclusion on the origin of SARS-CoV-2. 

What we know and what we need to know about the origin of SARS-CoV-2

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9420317

An updated review of the scientific literature on the origin of SARS-CoV-2

Hepatic ischemia-reperfusion injury (IRI) is an adverse consequence of hepatectomy or liver transplantation. Recently, immune mechanisms involved in hepatic IRI have attracted increased attention of investigators working in this area. In specific, group 2 innate lymphoid cells (ILC2s), have been strongly implicated in mediating type 2 inflammation. However, their immune mechanisms as involved with hepatic IRI remain unclear. Here, we reported that the population of ILC2s is increased with the development of hepatic IRI as shown in a mouse model in initial stage. Moreover, M2 type CD45+CD11b+F4/80high macrophages increased and reached maximal levels at 24 h followed by a significant elevation in IL-4 levels. We injected exogenous IL-33 into the tail vein of mice as a mean to stimulate ILC2s production. This stimulation of ILC2s resulted in a protective effect upon hepatic IRI along with an increase in M2 type CD45+CD11b+F4/80high macrophages. In contrast, depletion of ILC2s as achieved with use of an anti-CD90.2 antibody substantially abolished this protective effect of exogenous IL-33 and M2 type CD45+CD11b+F4/80high macrophage polarization in hepatic IRI. Therefore, this exogenous IL-33 induced potentiation of ILC2s appears to regulate the polarization of CD45+CD11b+F4/80high macrophages to alleviate IRI. Such findings provide the foundation for the development of new targets and strategies in the treatment of hepatic IRI.

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ILC2s expanded by exogenous IL-33 regulate CD45+CD11b+F4/80high macrophage polarization to alleviate hepatic ischemia-reperfusion injury

Group 2 innate lymphoid cells (ILC2s) were identified in 2010 as a novel lymphocyte subset lacking antigen receptors, such as T-cell or B-cell receptors. ILC2s induce local immune responses characterized by producing type 2 cytokines and play essential roles for maintaining tissue homeostasis. ILC2s are distributed across various organs, including the intestine where immune cells are continuously exposed to external antigens. Followed by luminal antigen stimulation, intestinal epithelial cells produce alarmins, such as IL-25, IL-33, and thymic stromal lymphopoietin, and activate ILC2s to expand and produce cytokines. In the context of parasite infection, the tuft cell lining in the epithelium has been revealed as a dominant source of intestinal IL-25 and possesses the capability to regulate ILC2 homeostasis. Neuronal systems also regulate ILC2s through neuropeptides and neurotransmitters, and interact with ILC2s bidirectionally, a process termed “neuro-immune crosstalk”. Activated ILC2s produce type 2 cytokines, which contribute to epithelial barrier function, clearance of luminal antigens and tissue repair, while ILC2s are also involved in chronic inflammation and tissue fibrosis. Recent studies have shed light on the contribution of ILC2s to inflammatory bowel diseases, mainly comprising ulcerative colitis and Crohn’s disease, as defined by chronic immune activation and inflammation. Modern single-cell analysis techniques provide a tissue-specific picture of ILC2s and their roles in regulating homeostasis in each organ. Particularly, single-cell analysis helps our understanding of the uniqueness and commonness of ILC2s across tissues and opens the novel research area of ILC2 heterogeneity. ILC2s are classified into different phenotypes depending on tissue and phase of inflammation, mainly inflammatory and natural ILC2 cells. ILC2s can also switch phenotype to ILC1- or ILC3-like subsets. Hence, recent studies have revealed the heterogeneity and plasticity of ILC2, which indicate dynamicity of inflammation and the immune system. In this review, we describe the regulatory mechanisms, function, and pathological roles of ILC2s in the intestine.

/pdf/heterogeneity-of-ilc2s-in-the-intestine-homeostasis-and-2yruyqys.pdf

Heterogeneity of ILC2s in the Intestine; Homeostasis and Pathology

Abstract Motivated by the up to now disastrous outcomes of the COVID-19 pandemic, we attempted a flashback to the so-called “Plague of Athens,” which indicated a serious contagious disease, having taken place between 430 and 426 BC. The ancient pandemic was meticulously described by the Athenian historian and general Thucydides. We compared, as much as possible, the following parameters: background conditions, spreading of the pandemics, preceded and concurrent adverse events, duration and waves of the pandemics, symptoms, implicated infectious agents/diseases and mental/psychosocial consequences. The current pandemic was preceded by a global economic crisis, which particularly affected deprived population groups, while the ancient one started on the second year of a catastrophic civil war. Rivalry and different political systems between now (US/China) and then (Athens/Sparta) superpowers were the basis for conspiracy scenarios, concerning origins of the pandemics, which resulted to huge numbers of deaths, particularly in overcrowded and poor areas/cities. Both pandemics not sparing any age, sex, nationality, social group, may have had a zoonotic component, besides being air-born. However, their spreading is/was remarkably rapid, presenting 3–4 waves and lasting for several years. Some somatic signs and symptoms of the diseases coincide. Although for COVID-19, SARS-CoV-2 has been identified as causing agent, the antique pandemic has most probably been attributed to typhoid fever, although this is still a matter of debate. Additionally, both pandemics affected mental health and psychosocial behavior in close similarity. It is noteworthy, that in both eras physicians and healthcare workers, despite physical and psychological exhaustion, in the majority, presented admirable resilience and willingness to help suffering fellow people, often at the expense of their own lives. The considerable number of comparable features between COVID-19 and the “Plague of Athens” confirms that pandemics may present over time important similarities in their origin, evolution and outcomes.

The COVID-19 pandemic and the “Plague of Athens”: comparable features 25 centuries apart

The COVID-19 pandemic is responsible for millions of deaths worldwide yet its origin remains unclear. Two potential scenarios of how infection of humans initially occurred include zoonotic transfer from wild animals and a leak of the pathogen from a research laboratory. The Wuhan wet markets where wild animals are sold represent a strong scenario for zoonotic transfer. However, isolation of SARS-CoV-2 or its immediate predecessor from wild animals in their natural environment has yet to be documented. Due to incomplete evidence for a zoonotic origin, a laboratory origin is plausible. The Wuhan Institute of Virology is at the epicenter of the pandemic and their work has included manipulation of wild-type coronavirus to enable infection of human cells. Although stronger evidence supports the zoonotic transfer, inconclusive reports maintain the laboratory leak hypothesis alive. It is imperative to reach a factual conclusion to prevent future pandemics.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/bies.202100189

The SARS-CoV-2 origin dilemma: Zoonotic transfer or laboratory leak?

Innate lymphoid cells (ILCs) are the most recently described group of lymphoid subpopulations. These tissue-resident cells display a heterogeneity resembling that observed on different groups of T cells, hence their categorization as cytotoxic NK cells and helper ILCs type 1, 2 and 3. Each one of these groups is highly diverse and expresses different markers in a context-dependent manner. Type 2 innate lymphoid cells (ILC2s) are activated in response to helminth parasites and regulate the immune response. They are involved in the etiology of diseases associated with allergic responses as well as in the maintenance of tissue homeostasis. Markers associated with their identification differ depending on the tissue and model used, making the study and understanding of these cells a cumbersome task. This review compiles evidence for the heterogeneity of ILC2s as well as discussion and analyses of molecular markers associated with their identity, function, tissue-dependent expression, and how these markers contribute to the interaction of ILC2s with specific microenvironments to maintain homeostasis or respond to pathogenic challenges.

/pdf/tissue-specific-molecular-markers-and-heterogeneity-in-type-3jh7u7jaa5.pdf

Blanca E. Ruiz-Medina

Papers

The SARS-CoV-2 origin dilemma: Zoonotic transfer or laboratory leak?

Tissue-Specific Molecular Markers and Heterogeneity in Type 2 Innate Lymphoid Cells.