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      Absent immune response to SARS-CoV-2 in a 3-month recurrence of coronavirus disease 2019 (COVID-19) case

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          Abstract

          Background

          The viral persistence in patients with Coronavirus Disease 2019 (COVID-19) remains to be investigated.

          Methods

          We investigated the viral loads, therapies, clinical features, and immune responses in a 70-year patient tested positive for SARS-CoV-2 for 3 months.

          Findings

          The patient exhibited the highest prevalence of abnormal indices of clinical features and immune responses at the first admission, including fever (38.3 ℃), decreased lymphocytes (0.83 × 10 9/L) and serum potassium (3.1 mmol/L), as well as elevated serum creatinine (115 µmol/L), urea (8.6 mmol/L), and C-reactive protein (80 mg/L). By contrast, at the second and the third admission, these indices were all normal. Through three admissions, IL-2 increased from 0.14 pg/mL, 0.69 pg/mL, to 0.91 pg/mL, while IL-6 decreased from 11.78 pg/mL, 1.52 pg/mL, to 0.69 pg/mL, so did IL-10 from 5.13 pg/mL, 1.85 pg/mL, to 1.75 pg/mL. The steady declining trend was also found in TNF-α (1.49, 1.15, and 0.85 pg/mL) and IFN-γ (0.64, 0.42, and 0.27 pg/mL). The threshold cycle values of RT-PCR were 26.1, 30.5, and 23.5 for ORFlab gene, and 26.2, 30.6, and 22.7 for N gene, showing the patient had higher viral loads at the first and the third admission than during the middle term of the disease. The patient also showed substantially improved acute exudative lesions on the chest CT scanning images.

          Conclusions

          The patient displayed declining immune responses in spite of the viral shedding for 3 months. We inferred the declining immune responses might result from the segregation of the virus from the immune system.

          Related collections

          Most cited references 12

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          IL-10, T cell exhaustion and viral persistence.

          Viral infections can have one of two outcomes: control of viral replication and acute infection or viral persistence and chronic infection. It is clear that both pathogen and host characteristics influence the acute versus chronic outcome of viral infection. The early events in the host immune response that favor immunosuppression and viral persistence, however, have remained poorly understood. Using the well-characterized mouse model of acute versus chronic lymphocytic choriomeningitis virus (LCMV) infection, two groups have recently identified the interleukin-10 (IL-10)/IL-10R pathway as a key regulator of acute versus chronic infection. Blockade of IL-10R converted a chronic LCMV infection into a rapidly controlled acute viral infection and prevented the functional exhaustion of memory T cells. These insights into the role of IL-10 in the establishment of chronic infection could lead to new therapeutic opportunities during human infections with pathogens such as HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV).
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            Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection.

            Effective T-cell responses are critical to eradicate acute viral infections and prevent viral persistence. Emerging evidence indicates that robust, early CD4 T-cell responses are important in effectively sustaining CD8 T-cell activity. Herein, we illustrate that virus-specific CD4 T cells are functionally inactivated early during the transition into viral persistence and fail to produce effector cytokines (i.e., interleukin-2 and tumor necrosis factor alpha), thereby compromising an efficient and effective antiviral immune response. Mechanistically, the inactivation occurs at the cellular level and is not an active process maintained by regulatory T cells or antigen-presenting cells. Importantly, a small subpopulation of cells is able to resist inactivation and persist into the chronic phase of infection. However, the virus-specific CD4 T-cell population ultimately undergoes a second round of inactivation, and the cells that had retained functional capacity fail to respond to rechallenge in an acute time frame. Based on these results we propose a biological mechanism whereby early CD4 T-cell inactivation leads to a subsequent inability to sustain cytotoxic T-lymphocyte function, which in turn facilitates viral persistence. Moreover, these studies are likely relevant to chronic/persistent infections of humans (e.g., human immunodeficiency virus, hepatitis C virus, and hepatitis B virus) by providing evidence that a reservoir of virus-specific CD4 T cells can remain functional during chronic infection and represent a potential therapeutic target to stimulate the immune response and establish control of infection.
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              Ablation of CD8 and CD4 T cell responses by high viral loads.

              To evaluate the impact of sustained viral loads on anti-viral T cell responses we compared responses that cleared acute lymphocytic choriomeningitis virus infection with those that were elicited but could not resolve chronic infection. During acute infection, as replicating virus was cleared, CD8 T cell responses were down-regulated, and a pool of resting memory cells developed. In chronically infected hosts, the failure to control the infection was associated with pronounced and prolonged activation of virus-specific CD8 T cells. Nevertheless, there was a progressive diminution of their effector activities as their capacity to produce first IL-2, then TNF-alpha, and finally IFN-gamma was lost. Chronic lymphocytic choriomeningitis virus infection was also associated with differential contraction of certain CD8 T cell responses, resulting in altered immunodominance. However, this altered immunodominance was not due to selective expansion of T cells expressing particular TCR Vbeta segments during chronic infection. High viral loads were not only associated with the ablation of CD8 T cell responses, but also with impaired production of IL-2 by virus-specific CD4 T cells. Taken together, our data show that sustained exposure to high viral loads results in the progressive functional inactivation of virus-specific T cell responses, which may further promote virus persistence.
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                Author and article information

                Contributors
                qifasong@126.com
                Journal
                Infection
                Infection
                Infection
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0300-8126
                1439-0973
                28 July 2020
                : 1-5
                Affiliations
                [1 ]Department of Clinical Laboratory, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
                [2 ]Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
                [3 ]Department of Blood Transfusion, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
                [4 ]Department of Acute Infectious Diseases. HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
                [5 ]Department of Experimental Medical Science, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
                [6 ]Department of Laboratory, Cixi Center for Disease Control and Prevention, Ningbo, China
                [7 ]Central Laboratory, Ningbo City First Hospital, Zhejiang Province, Ningbo, China
                Article
                1485
                10.1007/s15010-020-01485-6
                7386381
                © Springer-Verlag GmbH Germany, part of Springer Nature 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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