Alpha-synuclein dynamics bridge Type-I Interferon response and SARS-CoV-2 replication in peripheral cells.

BACKGROUND: Increasing evidence suggests a double-faceted role of alpha-synuclein (α-syn) following infection by a variety of viruses, including SARS-CoV-2. Although α-syn accumulation is known to contribute to cell toxicity and the development and/or exacerbation of neuropathological manifestations, it is also a key to sustaining anti-viral innate immunity. Consistently with α-syn aggregation as a hallmark of Parkinson's disease, most studies investigating the biological function of α-syn focused on neural cells, while reports on the role of α-syn in periphery are limited, especially in SARS-CoV-2 infection. RESULTS: Results herein obtained by real time qPCR, immunofluorescence and western blot indicate that α-syn upregulation in peripheral cells occurs as a Type-I Interferon (IFN)-related response against SARS-CoV-2 infection. Noteworthy, this effect mostly involves α-syn multimers, and the dynamic α-syn multimer:monomer ratio. Administration of excess α-syn monomers promoted SARS-CoV-2 replication along with downregulation of IFN-Stimulated Genes (ISGs) in epithelial lung cells, which was associated with reduced α-syn multimers and α-syn multimer:monomer ratio. These effects were prevented by combined administration of IFN-ß, which hindered virus replication and upregulated ISGs, meanwhile increasing both α-syn multimers and α-syn multimer:monomer ratio in the absence of cell toxicity. Finally, in endothelial cells displaying abortive SARS-CoV-2 replication, α-syn multimers, and multimer:monomer ratio were not reduced following exposure to the virus and exogenous α-syn, suggesting that only productive viral infection impairs α-syn multimerization and multimer:monomer equilibrium. CONCLUSIONS: Our study provides novel insights into the biology of α-syn, showing that its dynamic conformations are implicated in the innate immune response against SARS-CoV-2 infection in peripheral cells. In particular, our results suggest that promotion of non-toxic α-syn multimers likely occurs as a Type-I IFN-related biological response which partakes in the suppression of viral replication. Further studies are needed to replicate our findings in neuronal cells as well as animal models, and to ascertain the nature of such α-syn conformations.

Simplexviruses Successfully Adapt to Their Host by Fine-Tuning Immune Responses.

Primate herpes simplex viruses are species-specific and relatively harmless to their natural hosts. However, cross-species transmission is often associated with severe disease, as exemplified by the virulence of macacine herpesvirus 1 (B virus) in humans. We performed a genome-wide scan for signals of adaptation of simplexviruses to their hominin hosts. Among core genes, we found evidence of episodic positive selection in three glycoproteins, with several selected sites located in antigenic determinants. Positively selected noncore genes were found to be involved in different immune-escape mechanisms. The herpes simplex virus (HSV)-1/HSV-2 encoded product (ICP47) of one of these genes is known to down-modulate major histocompatibility complex class I expression. This feature is not shared with B virus, which instead up-regulates Human Leukocyte Antigen (HLA)-G, an immunomodulatory molecule. By in vitro expression of different ICP47 mutants, we functionally characterized the selection signals. Results indicated that the selected sites do not represent the sole determinants of binding to the transporter associated with antigen processing (TAP). Conversely, the amino acid status at these sites was sufficient to determine HLA-G up-regulation. In fact, both HSV-1 and HSV-2 ICP47 induced HLA-G when mutated to recapitulate residues in B virus, whereas the mutated version of B virus ICP47 failed to determine HLA-G expression. These differences might contribute to the severity of B virus infection in humans. Importantly, they indicate that the evolution of ICP47 in HSV-1/HSV-2 led to the loss of an immunosuppressive effect. Thus, related simplexviruses finely tune the balance between immunosuppressive and immunostimulatory pathways to promote successful co-existence with their primate hosts.

ERAPs Reduce In Vitro HIV Infection by Activating Innate Immune Response.

Recombinant human (rh) ERAP2-treated PBMCs are less susceptible to in vitro HIV-1 infection even when CD8+ T cells are depleted. We therefore investigated whether ERAP2 can trigger other immunocompetent cells, boosting their antiviral potential. To this end, human monocyte-derived macrophages (MDMs) differentiated from PBMCs of 15 healthy donors were in vitro HIV-1 infected in the presence/absence of 100 ng/ml of rhERAP2, rhERAP1, or rhERAP1+rhERAP2. Notably, rhERAP2 treatment resulted in a 7-fold reduction of HIV-1 replication in MDMs (p < 0.05). This antiviral activity was associated with an increased mRNA expression of CD80, IL-1ß, IL-18, and TNF-α (p < 0.01 for cytokine) in in vitro ERAP2-treated HIV-1-infected MDMs and a greater release of IL-1ß, TNF-α, IL-6, and IL-8 (p < 0.01 for each cytokine). The rhERAPs addition also induced the functional inflammasome activation by ASC speck formation in monocytes (p < 0.01) and in THP1-derived macrophages (p < 0.01) as well as a rise in the percentage of activated classical (CD14+CD16-HLA-DRII+CCR7+) and intermediate (CD14++CD16+HLA-DRII+CCR7+) monocytes (p < 0.02). Finally, THP-1-derived macrophages showed an increased phagocytosis following all ERAPs treatments. The discovery that ERAPs are able to trigger several antiviral mechanisms in monocyte/macrophages suggests that their anti-HIV potential is not limited to their canonical role in Ag presentation and CD8+ T cell activation. These findings pose the premise to further investigate the role of ERAPs in both innate and adaptive immunostimulatory pathways and suggest their potential use in novel preventive and therapeutic approaches against HIV-1 infection.

Salivary miRNA Profiles in COVID-19 Patients with Different Disease Severities.

The oral mucosa is the first site of SARS-CoV-2 entry and replication, and it plays a central role in the early defense against infection. Thus, the SARS-CoV-2 viral load, miRNAs, cytokines, and neutralizing activity (NA) were assessed in saliva and plasma from mild (MD) and severe (SD) COVID-19 patients. Here we showed that of the 84 miRNAs analyzed, 8 were differently expressed in the plasma and saliva of SD patients. In particular: (1) miRNAs let-7a-5p, let-7b-5p, and let-7c-5p were significantly downregulated; and (2) miR-23a and b and miR-29c, as well as three immunomodulatory miRNAs (miR-34a-5p, miR-181d-5p, and miR-146) were significantly upregulated. The production of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-8, IL-9, and TNFα) and chemokines (CCL2 and RANTES) increased in both the saliva and plasma of SD and MD patients. Notably, disease severity correlated with NA and immune activation. Monitoring these parameters could help predict disease outcomes and identify new markers of disease progression.

The Immunological Profile of SARS-CoV-2 Infection in Children Is Linked to Clinical Severity and Age.

Coronavirus disease 19 (COVID-19) is clinically less severe in children, even if the wide variety and degree of severity of symptoms reported in children pose a still-unresolved challenge for clinicians. We performed an in-depth analysis of the immunological profiles of 18 hospitalized SARS-CoV-2-infected children, whose results were compared to those obtained from 13 age- and sex-matched healthy controls (HC). The patients were categorized as paucisymptomatic/moderate (55.6%) or severe/critical (44.5%) according to established diagnostic criteria and further stratified into the categories of infants (1-12 months), children (1-12 years), and adolescents (>12 years). We assessed SARS-CoV-2-specific RBD antibodies (Ab), neutralizing antibodies (nAb), and circulating cytokines/chemokines in the plasma, and the SARS-CoV-2-specific immune response was measured in PBMCs by gene expression and secretome analyses. Our results showed peculiar circulating cytokine/chemokine profiles among patients sharing a similar clinical phenotype. A cluster of patients consisting of infants with severe symptoms presented hyperinflammatory profiles, together with extremely polarized antibody profiles. In a second cluster consisting of paucisymptomatic patients, a less pronounced increase in the level of inflammatory cytokines, together with an association between the selected cytokines and humoral responses, was observed. A third cluster, again consisting of paucisymptomatic patients, showed a circulating cytokine/chemokine profile which overlapped with that of the HC. The SARS-CoV-2-stimulated production of pro-inflammatory proteins, T lymphocyte activation, and migration-specific proteins, were significantly increased in SARS-CoV-2-infected children compared to the HC. Our findings suggest that immune response activation in the course of SARS-CoV-2 infection in children is directly correlated with clinical severity and, to a lesser extent, age.

Saliva and Plasma Neutralizing Activity Induced by the Administration of a Third bnt162b2 Vaccine Dose.

The BNT162b2 vaccine induces neutralizing activity (NA) in serum, but no data are available on whether a third-dose activates specific-immunity within the oral mucosa, representing the primary route of viral-entry. To carefully address this issue, we investigated if such immunity is boosted by SARS-CoV-2-infection; how long it is maintained over-time; and if it protects against the SARS-CoV-2 lineage B.1 (EU) and the emerging Delta and Omicron variants. NA was measured in plasma and saliva samples from: uninfected SARS-CoV-2-Vaccinated (SV), subjects infected prior to vaccination (SIV), and subjects who were infected after the second (SIV2) or the third (SIV3) vaccine dose. Samples were collected immediately before (T0), 15 days (T1), and 90 days (T2) post third-dose administration (SV and SIV), or 15 days post-infection (SIV2 and SIV3). In all the enrolled groups, NA in plasma and saliva: (i) was higher against EU compared to the other variants at all time-points (SV: T0 and T1, EU vs. both Delta and Omicron p < 0.001; T2 p < 0.01) (SIV: T0, EU vs. Delta p < 0.05; EU vs. Omi p < 0.01; T1 and T2 EU vs. Delta p < 0.01; EU vs. Omi p < 0.001); (ii) was boosted by the administration of the third dose; iii) declined over-time, albeit being detectable in almost all subjects at T2. The monitoring of NA over time will be important in clarifying if different NA levels may influence either acquisition or course of infection to properly plan the timing of a fourth vaccine dose administration.

A Knockout IFNL4 Variant Is Associated With Protection From Sexually Transmitted HIV-1 Infection.

An interferon λ4 gene (IFNL4) knockout allele (rs368234815; TT) is associated with spontaneous and IFN-α-dependent cure of hepatitis C virus infection. The role of this polymorphism in the susceptibility to human immunodeficiency virus type 1 (HIV-1) infection is controversial. This study aimed to assess the association of this knockout IFNL4 variant and sexually transmitted HIV-1 infection. A total of 228 HIV-1-positive individuals and 136 HIV-exposed seronegative individuals were investigated for their association with IFNL4 rs368234815 genotypes. The IFNL4 ΔG functional allele is associated with increased susceptibility to HIV-1 infection through the sexual route (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6; P = .004). A meta-analysis including a population of injection drug users suggests a codominant mode of inheritance of this risk factor (OR, 2.0; 95% CI, 1.3-3.2; P = .001).

Evolutionary analysis identifies an MX2 haplotype associated with natural resistance to HIV-1 infection.

The protein product of the myxovirus resistance 2 (MX2) gene restricts HIV-1 and simian retroviruses. We demonstrate that MX2 evolved adaptively in mammals with distinct sites representing selection targets in distinct branches; selection mainly involved residues in loop 4, previously shown to carry antiviral determinants. Modeling data indicated that positively selected sites form a continuous surface on loop 4, which folds into two antiparallel α-helices protruding from the stalk domain. A population genetics-phylogenetics approach indicated that the coding region of MX2 mainly evolved under negative selection in the human lineage. Nonetheless, population genetic analyses demonstrated that natural selection operated on MX2 during the recent history of human populations: distinct selective events drove the frequency increase of two haplotypes in the populations of Asian and European ancestry. The Asian haplotype carries a susceptibility allele for melanoma; the European haplotype is tagged by rs2074560, an intronic variant. Analyses performed on three independent European cohorts of HIV-1-exposed seronegative individuals with different geographic origin and distinct exposure route showed that the ancestral (G) allele of rs2074560 protects from HIV-1 infection with a recessive effect (combined P = 1.55 × 10(-4)). The same allele is associated with lower in vitro HIV-1 replication and increases MX2 expression levels in response to IFN-α. Data herein exploit evolutionary information to identify a novel host determinant of HIV-1 infection susceptibility.

Variants in the CYP7B1 gene region do not affect natural resistance to HIV-1 infection.

BACKGROUND: The genetic bases of natural resistance to HIV-1 infection remain largely unknown. Recently, two genome-wide association studies suggested a role for variants within or in the vicinity of the CYP7B1 gene in modulating HIV susceptibility. CYP7B1 is an appealing candidate for this due to its contribution to antiviral immune responses. We analyzed the frequency of two previously described CYP7B1 variants (rs6996198 and rs10808739) in three independent cohorts of HIV-1 infected subjects and HIV-1 exposed seronegative individuals (HESN). FINDINGS: rs6996198 and rs10808739 were genotyped in three case/control cohorts of sexually-exposed HESN and HIV-1-infected individuals from Italy, Peru and Colombia. Comparison of the allele and genotype frequencies of the two SNPs under different models showed that the only significant difference was seen for rs6996198 in the Peruvian sample (nominal p = 0.048, dominant model). For this variant, a random-effect meta-analysis yielded non-significant results (dominant model, p = 0.78) and revealed substantial heterogeneity among cohorts. No significant effect of the rs10808739 allelic status on HIV-1 infection susceptibility (additive model, p = 0.30) emerged from the meta-analysis. CONCLUSIONS: Although our study had limited power to detect association due to the small sample size, comparisons among the three cohorts revealed very similar allelic and genotypic frequencies in HESN and HIV-1 positive subjects. Overall, these data indicate that the two GWAS-defined variants in the CYP7B1 region do not strongly influence HIV-1 infection susceptibility.

A common polymorphism in TLR3 confers natural resistance to HIV-1 infection.

TLR3 recognizes dsRNA and activates antiviral immune responses through the production of inflammatory cytokines and type I IFNs. Genetic association studies have provided evidence concerning the role of a polymorphism in TLR3 (rs3775291, Leu412Phe) in viral infection susceptibility. We genotyped rs3775291 in a population of Spanish HIV-1-exposed seronegative (HESN) individuals who remain HIV seronegative despite repeated exposure through i.v. injection drug use (IDU-HESN individuals) as witnessed by their hepatitis C virus seropositivity. The frequency of individuals carrying at least one 412Phe allele was significantly higher in IDU-HESN individuals compared with that of a matched control sample (odds ratio for a dominant model = 1.87; 95% confidence interval, 1.06-3.34; p = 0.023). To replicate this finding, we analyzed a cohort of Italian, sexually HESN individuals. Similar results were obtained: the frequency of individuals carrying at least one 412Phe allele was significantly higher compared with that of a matched control sample (odds ratio, 1.79; 95% confidence interval, 1.05-3.08; p = 0.029). In vitro infection assays showed that in PBMCs carrying the 412Phe allele, HIV-1(Ba-L) replication was significantly reduced (p = 0.025) compared with that of Leu/Leu homozygous samples and was associated with a higher expression of factors suggestive of a state of immune activation (IL-6, CCL3, CD69). Similarly, stimulation of PBMCs with a TLR3 agonist indicated that the presence of the 412Phe allele results in a significantly increased expression of CD69 and higher production of proinflammatory cytokines including IL-6 and CCL3. The data of this study indicate that a common TLR3 allele confers immunologically mediated protection from HIV-1 and suggest the potential use of TLR3 triggering in HIV-1 immunotherapy.

Immunological Profiles in Parry-Romberg Syndrome: A Case-Control Study.

Background: Parry-Romberg syndrome (PRS) is a rare craniofacial disorder. The aim of this study is to provide information on the immunological profile of this pathology. Since PRS can be included in a wider spectrum of sclerodermic diseases, we propose a case-control study comparing a patient affected by PRS with one with a diagnosis of scleroderma, herein used as control (CTR). Methods: B lymphocyte, T lymphocyte, and monocyte phenotypes and functions were assessed by flow cytometry in influenza (Flu)- or anti cluster differentiation (CD)3/CD28-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine concentration was evaluated as well in PBMC supernatants, plasma, and saliva by Luminex assay. Results: T and B lymphocytes were similarly activated in unstimulated PRS and CTR cells but differed following antigen stimulation. T helper (Th)17 lymphocytes were expanded in PRS compared to CTR; this increase correlated with higher interleukin (IL)-17 concentration. Conclusions: Our case-control study is the first to compare the immunological profiles of PRS and scleroderma patients. The higher percentage of Th17 cells in PRS suggests the use of anti-IL17 receptor monoclonal antibody in this rare disease; however, further studies with larger numbers of patients are needed to confirm our findings.

The role of endoplasmic reticulum aminopeptidases in type 1 diabetes mellitus.

Type-I diabetes mellitus (T1DM) is generally considered as a chronic, T-cell mediated autoimmune disease. This notwithstanding, both the endogenous characteristics of ß-cells, and their response to environmental factors and exogenous inflammatory stimuli are key events in disease progression and exacerbation. As such, T1DM is now recognized as a multifactorial condition, with its onset being influenced by both genetic predisposition and environmental factors, among which, viral infections represent major triggers. In this frame, endoplasmic reticulum aminopeptidase 1 (ERAP1) and 2 (ERAP2) hold center stage. ERAPs represent the main hydrolytic enzymes specialized in trimming of N-terminal antigen peptides to be bound by MHC class I molecules and presented to CD8+ T cells. Thus, abnormalities in ERAPs expression alter the peptide-MHC-I repertoire both quantitatively and qualitatively, fostering both autoimmune and infectious diseases. Although only a few studies succeeded in determining direct associations between ERAPs variants and T1DM susceptibility/outbreak, alterations of ERAPs do impinge on a plethora of biological events which might indeed contribute to the disease development/exacerbation. Beyond abnormal self-antigen peptide trimming, these include preproinsulin processing, nitric oxide (NO) production, ER stress, cytokine responsiveness, and immune cell recruitment/activity. The present review brings together direct and indirect evidence focused on the immunobiological role of ERAPs in T1DM onset and progression, covering both genetic and environmental aspects.

Dopamine Reduces SARS-CoV-2 Replication In Vitro through Downregulation of D2 Receptors and Upregulation of Type-I Interferons.

Recent evidence suggests that SARS-CoV-2 hinders immune responses via dopamine (DA)-related mechanisms. Nonetheless, studies addressing the specific role of DA in the frame of SARS-CoV-2 infection are still missing. In the present study, we investigate the role of DA in SARS-CoV-2 replication along with potential links with innate immune pathways in CaLu-3 human epithelial lung cells. We document here for the first time that, besides DA synthetic pathways, SARS-CoV-2 alters the expression of D1 and D2 DA receptors (D1DR, D2DR), while DA administration reduces viral replication. Such an effect occurs at non-toxic, micromolar-range DA doses, which are known to induce receptor desensitization and downregulation. Indeed, the antiviral effects of DA were associated with a robust downregulation of D2DRs both at mRNA and protein levels, while the amount of D1DRs was not significantly affected. While halting SARS-CoV-2 replication, DA, similar to the D2DR agonist quinpirole, upregulates the expression of ISGs and Type-I IFNs, which goes along with the downregulation of various pro-inflammatory mediators. In turn, administration of Type-I IFNs, while dramatically reducing SARS-CoV-2 replication, converges in downregulating D2DRs expression. Besides configuring the CaLu-3 cell line as a suitable model to study SARS-CoV-2-induced alterations at the level of the DA system in the periphery, our findings disclose a previously unappreciated correlation between DA pathways and Type-I IFN response, which may be disrupted by SARS-CoV-2 for host cell invasion and replication.

Natural SARS-CoV-2 Infection Affects Neutralizing Activity in Saliva of Vaccinees.

Background: SARS-CoV-2 transmission mainly occurs through exposure of the upper airway mucosa to infected secretions such as saliva, which are excreted by an infected person. Thus, oral mucosal immunity plays a central role in the prevention of and early defense against SARS-CoV-2 infection. Although virus-specific antibody response has been extensively investigated in blood samples of SARS-CoV-2-infected patients and vaccinees, local humoral immunity in the oral cavity and its relationship to systemic antibody levels needs to be further addressed. Material and Methods: We fine-tuned a virus neutralization assay (vNTA) to measure the neutralizing activity (NA) of plasma and saliva samples from 20 SARS-CoV-2-infected (SI), 40 SARS-CoV-2-vaccinated (SV), and 28 SARS-CoV-2-vaccinated subjects with a history of infection (SIV) using the "wild type" SARS-CoV-2 lineage B.1 (EU) and the Delta (B.1.617.2) strains. To validate the vNTA results, the presence of neutralizing antibodies (NAbs) to the spike receptor binding domain (RBD) was evaluated with an ELISA assay. Results: NA to SARS-CoV-2 lineage B.1 (EU) was present in plasma samples from all the tested subjects, with higher titers in SIV compared to both SI and SV. Conversely, NA was detected in saliva samples from 10.3% SV, 45% SI, and 92.6% SIV, with significantly lower titers in SV compared to both SI and SIV. The detection of NAbs in saliva reflected its reduced NA in SV. Discussion: The difference in NA of plasma vs. saliva was confirmed in a vNTA where the SARS-CoV-2 B.1 and Delta strains were tested head-to-head, which also revealed a reduced NA of both specimens compared to the B.1 variant. Conclusions: The administration of SARS-CoV-2 vaccines was associated with limited virus NA in the oral cavity, as measured in saliva and in comparison to plasma. This difference was more evident in vaccinees without a history of SARS-CoV-2 infection, possibly highlighting the importance of local exposure at the site of virus acquisition to effectively prevent the infection and block its spread. Nevertheless, the presence of immune escape mutations as possibly represented by the SARS-CoV-2 Delta variant negatively affects both local and systemic efficacy of NA associated with vaccination.

Pregnant Women Develop a Specific Immunological Long-Lived Memory Against SARS-COV-2.

It is well established that pregnancy induces deep changes in the immune system. This is part of the physiological adaptation of the female organism to the pregnancy and the immunological tolerance toward the fetus. Indeed, over the three trimesters, the suppressive T regulatory lymphocytes are progressively more represented, while the expression of co-stimulatory molecules decreases overtime. Such adaptations relate to an increased risk of infections and progression to severe disease in pregnant women, potentially resulting in an altered generation of long-lived specific immunological memory of infection contracted during pregnancy. How potent is the immune response against SARS-CoV-2 in infected pregnant women and how long the specific SARS-CoV-2 immunity might last need to be urgently addressed, especially considering the current vaccinal campaign. To address these questions, we analyzed the long-term immunological response upon SARS-CoV-2 infection in pregnant women from delivery to a six-months follow-up. In particular, we investigated the specific antibody production, T cell memory subsets, and inflammation profile. Results show that 80% developed an anti-SARS-CoV-2-specific IgG response, comparable with the general population. While IgG were present only in 50% of the asymptomatic subjects, the antibody production was elicited by infection in all the mild-to-critical patients. The specific T-cell memory subsets rebalanced over-time, and the pro-inflammatory profile triggered by specific SARS-CoV-2 stimulation faded away. These results shed light on SARS-CoV-2-specific immunity in pregnant women; understanding the immunological dynamics of the immune system in response to SARS-CoV-2 is essential for defining proper obstetric management of pregnant women and fine tune gender-specific vaccinal plans.

No association of a risk variant for severe COVID-19 with HIV protection in three cohorts of highly exposed individuals.

An extended haplotype on chromosome 3 is the major genetic risk factor for severe COVID-19. The risk haplotype, which was inherited from Neanderthals, decreases the expression of several cytokine receptors, including CCR5. Recently, a study based on three general population cohorts indicated that the minor allele of one of the variants in the haplotype (rs17713054) protects against HIV infection. We thus expected this allele to be over-represented in highly exposed individuals who remain uninfected (exposed seronegative individuals, ESN). To perform a meta-analysis, we genotyped rs17713054 in three ESN cohorts of European ancestry exposed to HIV through different routes. No evidence of association was detected in the single cohorts. The meta-analysis also failed to detect any effect of the variant on protection from HIV-1. The same results were obtained in a Cox-regression analysis for the time to seroconversion. An in-vitro infection assay did not detect differences in viral replication as a function of rs17713054 genotype status. We conclude that the rs17713054 minor allele is not associated with the ESN phenotype and does not modulate HIV infection in vitro.

Antigen presentation in SARS-CoV-2 infection: the role of class I HLA and ERAP polymorphisms.

Given the highly polymorphic nature of Human Leukocyte Antigen (HLA) molecules, it is not surprising that they function as key regulators of the host immune response to almost all invading pathogens, including SARS-CoV-2, the etiological agent responsible for the recent COVID-19 pandemic. Several correlations have already been established between the expression of a specific HLA allele/haplotype and susceptibility/progression of SARS-CoV-2 infection and new ones are continuously emerging. Protective and harmful HLA variants have been described in both mild and severe forms of the disease, but considering the huge amount of existing variants, the data gathered in such a brief span of time are to some extent confusing and contradictory. The aim of this mini-review is to provide a snap-shot of the main findings so far collected on the HLA-SARS-CoV-2 interaction, so as to partially untangle this intricate yarn. As key factors in the generation of antigenic peptides to be presented by HLA molecules, ERAP1 and ERAP2 role in SARS-CoV-2 infection will be revised as well.

Unlikely SARS-CoV-2 Transmission During Vaginal Delivery.

Pregnant women display a higher risk of progression to disease and higher viral loads during infections due to their more permissive, tolerogenic immune system. However, only few studies have focused on SARS-CoV-2 intrapartum vertical transmission via vaginal secretions or faeces. The aim of this study was to investigate the presence of the virus in vaginal, rectal and blood specimens from pregnant women characterized by different COVID-19 disease severity. We enrolled 56 SARS-CoV-2-positive pregnant women, of which 46 (82%) were in the third trimester of pregnancy, 6 (10%) in the second and 4 (7%) in the first. QPCR was performed to detect the virus in vaginal and rectal swabs and in plasma samples. SARS-CoV-2 was detected in 27% of rectal swabs of pregnant women in the third trimester, while no virus particles were detected in vaginal swabs of the same patients. Furthermore, only 4% plasma samples tested positive to SARS-CoV-2. No virus was detected in newborn's nasopharyngeal swabs. Despite the low number of subjects enrolled, our data suggest that, while theoretically possible, intrapartum vaginal or orofecal SARS-CoV-2 transmission seems to be unlikely.

MiRNA Profiling in Plasma and Placenta of SARS-CoV-2-Infected Pregnant Women.

MicroRNAs are gene expression regulators associated with several human pathologies, including those generated by viral infections. Their role in SARS-CoV-2 infection and COVID-19 has been investigated and reviewed in many informative studies; however, a thorough miRNA outline in SARS-CoV-2-infected pregnant women (SIPW), at both systemic and placental levels, is missing. To fill this gap, blood and placenta biopsies collected at delivery from 15 asymptomatic SIPW were immediately analysed for: miRNA expression (n = 84) (QPCR array), antiviral/immune mRNA target expression (n = 74) (QGene) and cytokine/chemokines production (n = 27) (Multiplex ELISA). By comparing these results with those obtained from six uninfected pregnant women (UPW), we observed that, following SARS-CoV-2 infection, the transcriptomic profile of pregnant women is significantly altered in different anatomical districts, even in the absence of clinical symptoms and vertical transmission. This characteristic combination of miRNA and antiviral/immune factors seems to control both the infection and the dysfunctional immune reaction, thus representing a positive correlate of protection and a potential therapeutic target against SARS-CoV-2.

Immunological Characterization of HIV and SARS-CoV-2 Coinfected Young Individuals.

While the risk of SARS-CoV-2 infection and/or COVID-19 disease progression in the general population has been largely assessed, its impact on HIV-positive individuals remains unclear. We present clinical and immunological data collected in a cohort of HIV-infected young individuals during the first wave of COVID-19 pandemic. SARS-CoV-2 RNA, virus-specific antibodies, as well as the expression of factors involved in the anti-viral immune response were analyzed. Moreover, we set up an in vitro coinfection assay to study the mechanisms correlated to the coinfection process. Our results did not show any increased risk of severe COVID-19 in HIV-positive young individuals. In those subjects who contracted SARS-CoV-2 infection, an increase in IL-10 expression and production was observed. Furthermore, in the in vitro coinfection assay, we revealed a reduction in SARS-CoV-2 replication associated to an upregulation of IL-10. We speculate that IL-10 could play a crucial role in the course of SARS-CoV-2 infection in HIV-positive individuals. These results might help defining clinical management of HIV/SARS-CoV-2 co-infected young individuals, or putative indications for vaccination schedules in this population.