Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is considered a zoonotic pathogen mainly transmitted human to human. Few reports indicate that pets ...may be exposed to the virus. The present report describes a cat suffering from severe respiratory distress and thrombocytopenia living with a family with several members affected by COVID-19. Clinical signs of the cat prompted humanitarian euthanasia and a detailed postmortem investigation to assess whether a COVID-19–like disease was causing the condition. Necropsy results showed the animal suffered from feline hypertrophic cardiomyopathy and severe pulmonary edema and thrombosis. SARS-CoV-2 RNA was only detected in nasal swab, nasal turbinates, and mesenteric lymph node, but no evidence of histopathological lesions compatible with a viral infection were detected. The cat seroconverted against SARS-CoV-2, further evidencing a productive infection in this animal. We conclude that the animal had a subclinical SARS-CoV-2 infection concomitant to an unrelated cardiomyopathy that led to euthanasia.
Abstract
Unraveling the long-term kinetics of antibodies to SARS-CoV-2 and the individual characteristics influencing it, including the impact of pre-existing antibodies to human coronaviruses ...causing common cold (HCoVs), is essential to understand protective immunity to COVID-19 and devise effective surveillance strategies. IgM, IgA and IgG levels against six SARS-CoV-2 antigens and the nucleocapsid antigen of the four HCoV (229E, NL63, OC43 and HKU1) were quantified by Luminex, and antibody neutralization capacity was assessed by flow cytometry, in a cohort of health care workers followed up to 7 months (
N
= 578). Seroprevalence increases over time from 13.5% (month 0) and 15.6% (month 1) to 16.4% (month 6). Levels of antibodies, including those with neutralizing capacity, are stable over time, except IgG to nucleocapsid antigen and IgM levels that wane. After the peak response, anti-spike antibody levels increase from ~150 days post-symptom onset in all individuals (73% for IgG), in the absence of any evidence of re-exposure. IgG and IgA to HCoV are significantly higher in asymptomatic than symptomatic seropositive individuals. Thus, pre-existing cross-reactive HCoVs antibodies could have a protective effect against SARS-CoV-2 infection and COVID-19 disease.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet ...but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.
•The pathogenesis of ME/CFS is multifactorial, and immunological and environmental factors play a role.•Autoimmune mechanisms can be linked with ME/CFS at least in a subset of patients.•Autoantibodies mostly against nuclear and neurotransmitter receptors are found in a subset of ME/CFS patients.•Immunomodulatory therapeutic strategies targeting autoantibodies may be beneficial and should be pursued.
The protective effect of neutralizing antibodies in SARS-CoV-2 infected individuals is not yet well defined. To address this issue, we have analyzed the kinetics of neutralizing antibody responses ...and their association with disease severity. Between March and May 2020, the prospective KING study enrolled 72 COVID-19+ participants grouped according to disease severity. SARS-CoV-2 infection was diagnosed by serological and virological tests. Plasma neutralizing responses were assessed against replicative virus and pseudoviral particles. Multiple regression and non-parametric tests were used to analyze dependence of parameters. The magnitude of neutralizing titers significantly increased with disease severity. Hospitalized individuals developed higher titers compared to mild-symptomatic and asymptomatic individuals, which together showed titers below the detection limit in 50% of cases. Longitudinal analysis confirmed the strong differences in neutralizing titers between non-hospitalized and hospitalized participants and showed rapid kinetics of appearance of neutralizing antibodies (50% and 80% of maximal activity reached after 11 and 17 days after symptoms onset, respectively) in hospitalized patients. No significant impact of age, gender or treatment on the neutralizing titers was observed in this limited cohort. These data identify a clear association of humoral immunity with disease severity and point to immune mechanisms other than antibodies as relevant players in COVID-19 protection.
The magnitude and the quality of humoral responses against SARS-CoV-2 have been associated with clinical outcome. Although the elicitation of humoral responses against different viral proteins is ...rapid and occurs in most infected individuals, its magnitude is highly variable among them and positively correlates with COVID-19 disease severity. This rapid response is characterized by the almost concomitant appearance of virus-specific IgG, IgA and IgM antibodies that contain neutralizing antibodies directed against different epitopes of the Spike glycoprotein. Of particularly interest, the antibodies against domain of the Spike that interacts with the cellular receptor ACE2, known as the receptor binding domain (RBD), are present in most infected individuals and are block viral entry and infectivity. Such neutralizing antibodies protect different animal species when administered before virus exposure; therefore, its elicitation is the main target of current vaccine approaches and their clinical use as recombinant monoclonal antibodies (mAbs) is being explored. Yet, little information exists on the duration of humoral responses during natural infection. This is a key issue that will impact the management of the pandemic and determine the utility of seroconversion studies and the level of herd immunity. Certainly, several cases of reinfection have been reported, suggesting that immunity could be transient, as reported for other coronaviruses. In summary, although the kinetics of the generation of antibodies against SASR-CoV-2 and their protective activity have been clearly defined, their role in COVID-19 pathogenesis and the length of these responses are still open questions.
Human endogenous retroviruses and cancer Gonzalez-Cao, María; Iduma, Paola; Karachaliou, Niki ...
Cancer biology & medicine,
12/2016, Volume:
13, Issue:
4
Journal Article
Peer reviewed
Open access
Human endogenous retroviruses（HERVs） are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most ...of which are nonfunctional because of epigenetic control or deactivating mutations. However, a correlation between HERVs and human cancer has been described and many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K（HML6） and HERV-K（HML2）. Although the causative role of HERVs in cancer is controversial, data from animal models demonstrated that endogenous retroviruses are potentially oncogenic. HERV protein expression in human cells generates an immune response by activating innate and adaptive immunities. Some HERV-derived peptides have antigenic properties. For example, HERV-K（HML-6） encodes the HER-K MEL peptide recognized by CD8＋ lymphocytes. In addition, HERVs are twoedged immunomodulators. HERVs show immunosuppressive activity. The presence of genomic retroviral elements in host-cell cytosol may activate an interferon type I response. Therefore, targeting HERVs through cellular vaccines or immunomodulatory drugs combined with checkpoint inhibitors is attracting interest because they could be active in human tumors.
Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally ...believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.
The emerging SARS-CoV-2 variants of concern (VOCs) may display enhanced transmissibility, more severity and/or immune evasion; however, the pathogenesis of these new VOCs in experimental SARS-CoV-2 ...models or the potential infection of other animal species is not completely understood. Here we infected K18-hACE2 transgenic mice with B.1, B.1.351/Beta, B.1.617.2/Delta and BA.1.1/Omicron isolates and demonstrated heterogeneous infectivity and pathogenesis. B.1.351/Beta variant was the most pathogenic, while BA.1.1/Omicron led to lower viral RNA in the absence of major visible clinical signs. In parallel, we infected wildtype (WT) mice and confirmed that, contrary to B.1 and B.1.617.2/Delta, B.1.351/Beta and BA.1.1/Omicron can infect them. Infection in WT mice coursed without major clinical signs and viral RNA was transient and undetectable in the lungs by day 7 post-infection.
modeling supported these findings by predicting B.1.351/Beta receptor binding domain (RBD) mutations result in an increased affinity for both human and murine ACE2 receptors, while BA.1/Omicron RBD mutations only show increased affinity for murine ACE2.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory disease, but it can also affect other organs including the central nervous system. Several animal models have been ...developed to address different key questions related to Coronavirus Disease 2019 (COVID-19). Wild-type mice are minimally susceptible to certain SARS-CoV-2 lineages (beta and gamma variants), whereas hACE2-transgenic mice succumb to SARS-CoV-2 and develop a fatal neurological disease. In this article, we aimed to chronologically characterize SARS-CoV-2 neuroinvasion and neuropathology. Necropsies were performed at different time points, and the brain and olfactory mucosa were processed for histopathological analysis. SARS-CoV-2 virological assays including immunohistochemistry were performed along with a panel of antibodies to assess neuroinflammation. At 6 to 7 days post inoculation (dpi), brain lesions were characterized by nonsuppurative meningoencephalitis and diffuse astrogliosis and microgliosis. Vasculitis and thrombosis were also present and associated with occasional microhemorrhages and spongiosis. Moreover, there was vacuolar degeneration of virus-infected neurons. At 2 dpi, SARS-CoV-2 immunolabeling was only found in the olfactory mucosa, but at 4 dpi intraneuronal virus immunolabeling had already reached most of the brain areas. Maximal distribution of the virus was observed throughout the brain at 6 to 7 dpi except for the cerebellum, which was mostly spared. Our results suggest an early entry of the virus through the olfactory mucosa and a rapid interneuronal spread of the virus leading to acute encephalitis and neuronal damage in this mouse model.
Promptly after primoinfection, HIV generates a pool of infected cells carrying transcriptionally silent integrated proviral DNA, the HIV-1 reservoir. These cells are not cleared by combined ...antiretroviral therapy (cART), and persist lifelong in treated HIV-infected individuals. Defining clinical strategies to eradicate the HIV reservoir and cure HIV-infected individuals is a major research field that requires a deep understanding of the mechanisms of seeding, maintenance and destruction of latently infected cells. Although CTL responses have been classically associated with the control of HIV replication, and hence with the size of HIV reservoir, broadly neutralizing antibodies (bNAbs) have emerged as new players in HIV cure strategies. Several reasons support this potential role: (i) over the last years a number of bNAbs with high potency and ability to cope with the extreme variability of HIV have been identified; (ii) antibodies not only block HIV replication but mediate effector functions that may contribute to the removal of infected cells and to boost immune responses against HIV; (iii) a series of new technologies have allowed for the
design of improved antibodies with increased antiviral and effector functions. Recent studies in non-human primate models and in HIV-infected individuals have shown that treatment with recombinant bNAbs isolated from HIV-infected individuals is safe and may have a beneficial effect both on the seeding of the HIV reservoir and on the inhibition of HIV replication. These promising data and the development of antibody technology have paved the way for treating HIV infection with engineered monoclonal antibodies with high potency of neutralization, wide coverage of HIV diversity, extended plasma half-life
and improved effector functions. The exciting effects of these newly designed antibodies
, either alone or in combination with other cure strategies (latency reversing agents or therapeutic vaccines), open a new hope in HIV eradication.
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