Regulatory T cells: A potential weapon to combat COVID‐19? - Wiley

2.1.1 Early pathological changes in SARS‐CoV‐2‐infected pneumonia

The pathology data of COVID‐19 could be obtained by autopsies. Xiao and colleagues reported two lung cancer patients who were later diagnosed as COVID‐19 infected.4 When the superimposed infections were not recognized, lung tumors of the two patients were obtained by surgeries.4

The surgical specimens were presumed at the early phase of SARS‐CoV‐2 infection. The histopathology of surgical specimens showed inflammatory infiltrate and pneumocyte hyperplasia in the absence of obvious hyaline membrane formation, squamous metaplasia, and tissue remodeling consistent with proliferative and exudative features of acute lung injury (ALI).4 However, the mechanisms underlying pathogenesis of COVID‐19 are so far not fully understood.

2.1.2 Later pathological changes in SARS‐CoV‐2‐infected pneumonia

Xu et al5 were the first to report the pathological characteristics of a person who died from COVID‐19 by examining biopsy samples obtained at autopsy. The patient was a 50‐year‐old man whose chest showed many patchy shadows in right and left lungs by X‐ray.5 The histopathology of both lungs exhibited diffuse alveolar injury with fibromyxoid secretions.5 In addition to this, both lung tissues revealed desquamation of pneumocytes and hyaline membrane formation. The report pointed out that in the intra‐alveolar spaces of autopsy tissues emerged multinucleated syncytial cells with amphiphilic granular cytoplasm and enlarged pneumocytes, a characteristic of viral cytopathic‐like changes. In short, multinucleated giant cells and inflammatory cells were prominently observed within the interspace in the absence of any significant neutrophil infiltration in tissues. The report also demonstrated that the number of CD4 T cells and CD8 T cells were substantially decreased, whereas Th17 and CD8 cytotoxic T cells were significantly grown in the peripheral blood.5 Wan et al data also showed decreasing level of NK cells CD8⁺ T cells, B cells, and CD4⁺ T cells, and elevated levels of serum IL‐10 and IL‐6 in peripheral blood lymphocyte of SARS‐CoV‐2‐infected patients (unpublished). Another report by Huang et al6 showed that compared to healthy subjects, the initial levels of plasma IL‐10, IL‐8, IL‐1Rα, IL‐7, IL‐1β, IL‐9, basic FGF, GM‐CSF, G‐CSF, IP10, MIP1A, MIP1B, MCP1, IFN‐γ, TNF‐α, PDGF, and VEGF were higher in SARS‐CoV‐2‐infected patients than controls.6 Moreover, higher plasma levels of IL‐10, IL‐7, IL‐2, G‐SCF, MIP1A, MCP1, IP10, and TNF‐α were also observed in more severely affected patients assigned to an ICU than that non‐ICU patients.6 Such a mechanism was suggested by Huang et al7 in a study of SARS patients in which 14 chemokines or cytokines were analyzed on 88 RT‐PCR‐confirmed SARS‐CoV patients. The report showed that although TNF‐α, IL‐10, TNFRI, IL‐2, IL‐13, or IL‐4 levels were normal, the levels of IL‐18, IL‐8, IL‐6, IP‐10, IFN‐γ, MIG, TGF‐β, and MCP‐1 were highly increased in serum of the early phase of Taiwan SARS‐CoV patients. The authors concluded that an IL‐6‐, IFN‐γ‐, and IL‐8‐related inflammatory storm was excited after SARS‐CoV infection, and this inflammatory storm might cause immunopathological damage in SARS‐CoV patients. Therefore, it is reasonable to conclude that the clinical deterioration of patients infected with SARS‐CoV‐2 is perhaps due to increased systemic cytokine levels known as cytokine storm. The main changes in the microenvironment of infected pulmonary tissue include accumulating lots of NK cells, macrophages (mainly be type I macrophage), B cells, and dendritic cells, which can recruit and contribute to the activation of CD8 T and CD4 T cells (Figure 1). These cells will directly affect or secret above‐mentioned inflammatory factors to eliminate coronavirus but also cause lung inflammation and injury. At the same time, amount of natural regulatory T cell (nTreg) and induced regulatory T cell (iTreg) will be chelated to infected pulmonary tissue to inhibit excessive inflammation and repair the tissue (Figure 1). When the infection is serious, a bunch of inflammatory factors will form inflammatory storm and the pulmonary tissue damage, and the function of Treg cells will be then reduced or diminished.

Immune response in lung tissues after coronavirus infection. When lung tissue is infected with coronavirus, NK cells, macrophages, and antigen‐presenting cells are recruited to the tissue to produce inflammatory factors and then active CD8 and CD4 T cells for combat coronavirus. When the infection is serious, these inflammatory factors will form inflammatory cytokines storm to injury the tissue. TNF‐α, IL‐1β, IL‐6, and IL‐8 are considered the main components of cytokine‐storm. TNF‐α would be produced by NK cells, macrophages, and activated CD4 and CD8 T cells. IL‐1β and IL‐8 are secreted by macrophages. IL‐6 could be produced by inflammatory macrophages. At the same time, T cells also secrete IFN‐γ to fight the coronavirus. On the opposite side, Treg and type II macrophage could secret IL‐10 and TGF‐β, which then reduce inflammatory response. In addition, TGF‐β participates in the tissue repair process

2.1.3 Treatment of SARS‐CoV‐2 pneumonia

Until now, no specific antiviral approach is validated to cure the patients of SARS‐CoV‐2 infection except for fine patient care. Currently, the most effective method to this infectious pneumonia is to block the origin of infection. Second is to take personal protection measures and provide early diagnosis and treatment for affected people.8, 9 Use of an antiviral therapeutic regimen consisting of an anti‐HIV drug combination of ritonavir and lopinavir together with intranasal nebulized IFN‐α at appropriate drug dosages was suggested by China's National Health Commission, and the guidance is dependent on and determined by disease severity.10, 11 Antibacterial agents are not only ineffective, but importantly, often cause serious acute respiratory distress syndrome.7 There are more than 200 clinical trials in SARS‐CoV‐2 patients with antivirus agents in China, and none has demonstrated any significantly therapeutic effect on patients with COVID‐19. Hence, an effective treatment strategy for COVID‐19 is urgent needed.

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2020-08-07 02:25:24Z
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