Innate antiviral defense demonstrates high energetic efficiency in a bony fish

Background Viruses can impose energetic demands on organisms they infect, in part by hosts mounting resistance. Recognizing that oxygen uptake reliably indicates steady-state energy consumption in all vertebrates, we comprehensively evaluated oxygen uptake and select transcriptomic messaging in sockeye salmon challenged with either a virulent rhabdovirus (IHNV) or a low-virulent reovirus (PRV). We tested three hypotheses relating to the energetic costs of viral resistance and tolerance in this vertebrate system: (1) mounting resistance incurs a metabolic cost or limitation, (2) induction of the innate antiviral interferon system compromises homeostasis, and (3) antiviral defenses are weakened by acute stress. Results IHNV infections either produced mortality within 1–4 weeks or the survivors cleared infections within 1–9 weeks. Transcription of three interferon-stimulated genes (ISGs) was strongly correlated with IHNV load but not respiratory performance. Instead, early IHNV resistance was associated with a mean 19% (95% CI = 7–31%; p = 0.003) reduction in standard metabolic rate. The stress of exhaustive exercise did not increase IHNV transcript loads, but elevated host inflammatory transcriptional signaling up to sevenfold. For PRV, sockeye tolerated high-load systemic PRV blood infections. ISG transcription was transiently induced at peak PRV loads without associated morbidity, microscopic lesions, or major changes in aerobic or anaerobic respiratory performance, but some individuals with high-load blood infections experienced a transient, minor reduction in hemoglobin concentration and increased duration of excess post-exercise oxygen consumption. Conclusions Contrary to our first hypothesis, effective resistance against life-threatening rhabdovirus infections or tolerance to high-load reovirus infections incurred minimal metabolic costs to salmon. Even robust systemic activation of the interferon system did not levy an allostatic load sufficient to compromise host homeostasis or respiratory performance, rejecting our second hypothesis that this ancient innate vertebrate antiviral defense is itself energetically expensive. Lastly, an acute stress experienced during testing did not weaken host antiviral defenses sufficiently to promote viral replication; however, a possibility for disease intensification contingent upon underlying inflammation was indicated. These data cumulatively demonstrate that fundamental innate vertebrate defense strategies against potentially life-threatening viral exposure impose limited putative costs on concurrent aerobic or energetic demands of the organism.

NS1: A Key Protein in the “Game” Between Influenza A Virus and Host in Innate Immunity

Since the influenza pandemic occurred in 1918, people have recognized the perniciousness of this virus. It can cause mild to severe infections in animals and humans worldwide, with extremely high morbidity and mortality. Since the first day of human discovery of it, the “game” between the influenza virus and the host has never stopped. NS1 protein is the key protein of the influenza virus against host innate immunity. The interaction between viruses and organisms is a complex and dynamic process, in which they restrict each other, but retain their own advantages. In this review, we start by introducing the structure and biological characteristics of NS1, and then investigate the factors that affect pathogenicity of influenza which determined by NS1. In order to uncover the importance of NS1, we analyze the interaction of NS1 protein with interferon system in innate immunity and the molecular mechanism of host antagonism to NS1 protein, highlight the unique biological function of NS1 protein in cell cycle.

ANALYSIS OF INTERFERON-I SIGNALING ACTIVITY IN CHILDREN WITH SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS OF A PILOT PROSPECTIVE STUDY

The interferon system (IFN) is a group of signaling molecules with antiviral, antitumor and antiproliferative effects. The most studied signaling pathway is mediated by IFN type I. Mutations of IFN-I-regulated genes are involved in the pathogenesis of systemic lupus erythematosus (SLE). Interferon index (IFN-I-index) – a quantitative indicator of the level of expression of IFN-Iregulated genes – is used to assess the activity of the interferon system. Objective of the study: to assess the level of the IFN-I index in children with SLE, as well as to compare the clinical and laboratory characteristics of patients with high and normal levels of the IFN-I-index. Materials and methods of research: 40 patients (girls – 83%, boys – 17%) under 18 years of age with SLE diagnosed in accordance to the SLICC 2012 criteria were included in a multicenter prospective open uncontrolled nonrandomized continuous study. The age of the patients was 15,2 (12,5 ; 16,7) years. All of them underwent examination and treatment in the Pediatric department № 3 at the clinic of the St. Petersburg State Pediatric Medical University and in the Pediatric department of the Almazov National Medical Research Center. The IFN-I index was determined by real-time PCR with a quantitative assessment of the expression of 5 genes induced by IFN-α and β. Results: aggravated family history of rheumatic diseases was noted in 8 patients: SLE – in 3 (8%), rheumatoid arthritis – in 3 (8%), cold urticaria – in 2 (5%). The average age of onset of the disease is 12 years. The most common clinical manifestations were lesions of the skin, joints, mucous membranes, central nervous system, kidney and fever. 31 patients (78%) had an increased IFN-I index. All cases of kidney failure were observed only in patients with a high IFN index (36% vs 0%, p=0,036). Patients with increased IFN-I-index had statistically significant increased levels of antinuclear (87% vs 56%, p=0,043) and rheumatoid factors (36% vs 0%, p=0,036), higher ECLAM index values (3,0 vs 1.0, p=0,048), ferritin levels (p=0,0008) and, as a consequence, the need for more intensive immunosuppressive therapy (using rituximab and cyclophosphamide) compared with patients with normal IFN-Iindex. A positive statistically significant correlation of the IFN-I index with male sex (r=0,41, p=0,008), nephritis (r=0,35, p=0,026), livedoid rash (r=0,38, p=0,017 ), Raynaud's phenomenon (r=0,37, p=0,018), high antinuclear factor (r=0,82, p=0,001), rheumatoid factor (r=0,654, p=0,011), antibodies to Sm antigen (r=0,57, p=0,034), as well as a negative relationship with anemia (r=–0,67, p=0,009). Conclusion: IFN-I-index can be considered as a surrogate biomarker of activity and prognosis of SLE. Further research is required to validate its diagnostic role.

Comparing Expression of OAS-RNaseL Pathway-Related Genes in SARS-CoV-2 and Similar Viruses

The COVID-19 pandemic, caused by the virus SARS-CoV-2, has been a major public health emergency and has caused millions of deaths worldwide to date. Due to the novel nature of the virus, efforts across the world are underway to better understand the molecular pathogenesis of SARS-CoV-2 and how it interacts with host immune responses. One important branch of the innate immune response, the interferon system, triggers the expression of many effector mechanisms known to be powerful antagonists against many pathogenic viruses. One such interferon stimulated mechanism is the OAS-RNaseL pathway, which is known to trigger the degradation of viral RNA in infected host cells. Our study seeks to utilize publicly available transcriptomic data to analyze the host cell OAS-RNaseL pathway to SARS-CoV-2 infection. We hoped to gain an understanding of the importance of the pathway in controlling SARS-CoV-2 infection and whether or not the pathway could be exploited therapeutically. Our findings demonstrated that upregulation of OAS-RNaseL pathway genes in response to SARS-CoV-2 infection varies based on cell type and appeared to correlate with ACE2 receptor expression. Pathway responses to other viruses like SARS-CoV and MERS-CoV were found to parallel those to SARS-CoV-2, suggesting common response patterns by the pathway to these viruses. Overall, these results demonstrate that the OAS-RNaseL pathway could contribute to control of SARS-CoV-2 infection. Further studies on various mechanistic actions by the pathway would need to be conducted to fully understand its role in host defense and therapy.

CLINICAL AND IMMUNOLOGICAL FEATURES OF INFLAMMATORY DISEASES OF THE PELVIS AND GENITAL ORGANS IN HIV-INFECTED WOMEN

The aim of the study is to study the cytokine profile in HIV-infected women with acute vaginitis against the background of complex conservative treatment. Materials and methods of research 55 women aged from 25 to 55 years with acute vaginitis were under our supervision. All women were surveyed for the period from 2018 to 2020, of which 35 women with HIV infection, which constitutes the main group, and 20 women without HIV infection, which constitutes the control group. In all female patients, cytokines (to determine inflammatory processes) (IFNγ, IL-17) were determined in the peripheral blood serum. IFNγ, IL-17 were determined by enzyme-linked immunosorbent assay using test systems "Vector-Best" of the Russian Federation. Results and discussion: the ratio of IFNγ / IL-17 (pro-inflammatory / anti-inflammatory cytokines or Th1 / Th2) in HIV-uninfected women was 2.2. In the presence of a pronounced inflammatory process, that is, in HIV-uninfected women, this indicator was 0.96. After carrying out immunocorrective treatment using Immun-5 (The drug is a balanced mixture of natural biologically active substances, the action of which is aimed at activating the body's immune system. The drug increases the body's resistance in inflammatory diseases. An effective remedy for HIV / AIDS, hepatitis and tuberculosis. 1 capsule 2 times a day for 60 days The drug manifests its effects primarily through the effect on the endogenous interferon system and on the expression of cytokines functionally coupled with interferons - IL-2, IL-4, IL-6, IL-10 and IL-17). In the examined HIV-infected women with nonspecific vaginitis, IFNγ approached the control values, the content of IL-17, and after treatment did not normalize, remaining 5.5 times higher than in HIV-uninfected women in the control group, the ratio of IFNγ / IL-17, in HIV-infected women of the main group, after treatment this indicator decreased to 0.42. Conclusion: The improvement in the clinical condition of HIV-infected women, along with the suppression of the level of the pro-inflammatory cytokine IFNγ, was accompanied by the disappearance of signs of inflammation of the genitalia, an improvement in the general condition of HIV-infected women.

Herpetic infection in otorhinolaryngology as a multimorbidity factor

The search for common links of etiology and pathogenesis in the formation of comorbid pathology in modern patients opens up additional opportunities for increasing the effectiveness of their treatment and is an important problem in scientific and practical medicine. The extreme prevalence of chronic persistence of immunotropic viruses, such as herpes genotypes 4,5,6 types, requires a study of its consequences in the human body and the involvement in its infectious-dependent morbidity, such as the formation of multiple chronic foci of infection in the ear, nose and throat with frequent and prolonged exacerbations. The work shows that chronic sinusitis, nasopharyngitis, tonsillitis associated with chronic herpesvirus persistence form the status of frequently and long-term ill people against the background of pronounced immuno-compromise with quantitative and functional T- and B-cell deficiency, insufficient resources of α and γ- interferon. The study presents a positive experience of replenishing the deficiency of α and γ-interferons with recombinant drugs of the same name in comorbid ENT patients. The aim of the study was to increase the efficiency of treatment of patients with concomitant chronic focal infection in the ear, nose and throat against the background of chronic persistence of herpesvirus infection. Materials and methods: Comprehensive clinical and laboratory examination of 45 carriers of herpes simplex virus genotypes 4,5, 6 at the age of 29 to 52 years made it possible to establish in them a comorbid chronic focal infection in the LOR organs: chronic sinusitis, chronic nasopharyngitis, chronic tonsillitis. Results: The observed patients had a statistically significant (p < 0.01) deficiency of NK cells with receptors CD16+, CD56+ and B cells with markers CD19+, CD5+ against the background of peripheral blood lymphocytosis with an increase in the content of cytotoxic T lymphocytes (CD8 +) marker in some patients. All patients showed a significant decrease in interferon system resources (p < 0.01). Replacement therapy with recombinant preparations of α- and γ-interferons led to restoration of interferon system parameters and was accompanied by improvement of immunological blood indices, both quantitative and functional characteristics of T-and B-lymphocytes, mononuclear phagocytes, this dynamics was matched by improvement of patients, confirmed by results of questionnaire. Conclusions: Thus, the positive experience of antiviral therapy by restoring the resources of the interferon system and immune recovery with recombinant interferon drugs indicates the important role of herpes virus carrier in the formation of comorbidity and the need for etiological treatment to improve the condition and quality of life of patients.