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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a global cause of death. Granuloma-associated lymphoid tissue (GrALT) correlates with protection during TB, but the mechanisms of protection are not understood. During TB, the transcription factor IRF4 in T cells but not B cells is required for the generation of the TH1 and TH17 subsets of helper T cells and follicular helper T (TFH)-like cellular responses. A population of IRF4+ T cells coexpress the transcription factor BCL6 during Mtb infection, and deletion of Bcl6 (Bcl6fl/fl) in CD4+ T cells (CD4cre) resulted in reduction of TFH-like cells, impaired localization within GrALT and increased Mtb burden. In contrast, the absence of germinal center B cells, MHC class II expression on B cells, antibody-producing plasma cells or interleukin-10-expressing B cells, did not increase Mtb susceptibility. Indeed, antigen-specific B cells enhance cytokine production and strategically localize TFH-like cells within GrALT via interactions between programmed cell death 1 (PD-1) and its ligand PD-L1 and mediate Mtb control in both mice and macaques.
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Mycobacterium tuberculosis , Tuberculose , Camundongos , Animais , Linfócitos T Auxiliares-Indutores , Linfócitos B , Tecido Linfoide , Centro Germinativo , Fatores de TranscriçãoRESUMO
Neuraminidase (NA) is one of the two influenza virus surface glycoproteins, and antibodies that target it are an independent correlate of protection. However, our current understanding of NA antigenicity is incomplete. Here, we describe human monoclonal antibodies (mAbs) from a patient with a pandemic H1N1 virus infection in 2009. Two mAbs exhibited broad reactivity and inhibited NA enzyme activity of seasonal H1N1 viruses circulating before and after 2009, as well as viruses with avian or swine N1s. The mAbs provided robust protection from lethal challenge with human H1N1 and avian H5N1 viruses in mice, and both target an epitope on the lateral face of NA. In summary, we identified two broadly protective NA antibodies that share a novel epitope, inhibited NA activity, and provide protection against virus challenge in mice. Our work reaffirms that NA should be included as a target in future broadly protective or universal influenza virus vaccines.
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Anticorpos Monoclonais , Anticorpos Antivirais , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Neuraminidase , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/metabolismo , Anticorpos Antivirais/isolamento & purificação , Anticorpos Antivirais/metabolismo , Neuraminidase/química , Neuraminidase/metabolismo , Humanos , Fragmentos Fab das Imunoglobulinas/química , Microscopia Crioeletrônica , Epitopos , Camundongos Endogâmicos BALB C , Animais , Camundongos , Influenza Humana/tratamento farmacológico , Modelos Animais de DoençasRESUMO
OBJECTIVES: SSc is a devastating autoimmune disease characterized by fibrosis and obliterative vasculopathy affecting the skin and visceral organs. While the processes mediating excessive extracellular matrix deposition and fibroblast proliferation are clear, the exact link between autoimmunity and fibrosis remains elusive. Th17 cells have been proposed as critical drivers of profibrotic inflammation during SSc, but little is known about the immune components supporting their pathogenic role. Our aim was to determine cytokine responses of stimulated monocyte-derived dendritic cells (Mo-DCs) and to determine how they influence T-cell cytokine production in SSc. MATERIAL AND METHODS: Dendritic cells (DCs) activate and shape T cell differentiation by producing polarizing cytokines. Hence, we investigated the cytokine responses of monocyte-derived DCs (Mo-DCs) from patients with limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc) and healthy controls (HCs) after stimulation with toll-like receptor (TLR) agonists. Also, using co-culture assays, we analysed T cell subpopulations after contact with autologous TLR-activated Mo-DCs. RESULTS: In general, we observed an increased production of Th17-related cytokines like IL-1ß, IL-17F, IL-21 and IL-22 by SSc compared with HC Mo-DCs, with variations between lcSSc vs dcSSc and early- vs late-stage subgroups. Noticeably, we found a significant increment in IL-33 production by Mo-DCs in all SSc cases regardless of their clinical phenotype. Strikingly, T cells displayed Th2, Th17 and dual Th2-Th17 phenotypes after exposure to autologous TLR-stimulated Mo-DCs from SSc patients but not HCs. These changes were pronounced in individuals with early-stage dcSSc and less significant in the late-stage lcSSc subgroup. CONCLUSIONS: Our findings suggest that functional alterations of DCs promote immune mechanisms favouring the aberrant T cell polarization and profibrotic inflammation behind clinical SSc heterogeneity.
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Escleroderma Sistêmico , Humanos , Citocinas , Fibrose , Células Dendríticas/patologia , InflamaçãoRESUMO
Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or seasonal influenza may lead to respiratory failure requiring intubation and mechanical ventilation. The pathophysiology of this respiratory failure is attributed to local immune dysregulation, but how the immune response to viral infection in the lower airways of the human lung differs between individuals with respiratory failure and those without is not well understood. We used quantitative multiparameter flow cytometry and multiplex cytokine assays to evaluate matched blood and bronchoalveolar lavage (BAL) samples from control human subjects, subjects with symptomatic seasonal influenza who did not have respiratory failure, and subjects with severe seasonal influenza or SARS-CoV-2 infection with respiratory failure. We find that severe cases are associated with an influx of nonclassical monocytes, activated T cells, and plasmablast B cells into the lower airways. Cytokine concentrations were not elevated in the lower airways of moderate influenza patients compared with controls; however, 28 of 35 measured cytokines were significantly elevated in severe influenza, severe SARS-CoV-2 infection, or both. We noted the largest elevations in IL-6, IP-10, MCP-1, and IL-8. IL-1 family cytokines and RANTES were higher in severe influenza infection than severe SARS-CoV-2 infection. Interestingly, only the concentration of IP-10-correlated between blood and BAL during severe infection. Our results demonstrate inflammatory immune dysregulation in the lower airways during severe viral pneumonia that is distinct from lower airway responses seen in human patients with symptomatic, but not severe, illness and suggest that measurement of blood IP-10 concentration may predict this unique dysregulation.
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COVID-19/imunologia , Vírus da Influenza A/fisiologia , Pneumonia Viral/imunologia , Sistema Respiratório/imunologia , SARS-CoV-2/fisiologia , Adulto , Idoso , Proteínas Sanguíneas/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/diagnóstico , Quimiocina CXCL10/metabolismo , Estudos de Coortes , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Influenza Humana/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Respiratória , Índice de Gravidade de DoençaRESUMO
Central nervous system (CNS) infections including meningitis and encephalitis, resulting from the blood-borne spread of specific microorganisms, provoke nervous tissue damage due to the inflammatory process. Moreover, different pathologies such as sepsis can generate systemic inflammation. Bacterial lipopolysaccharide (LPS) induces the release of inflammatory mediators and damage molecules, which are then released into the bloodstream and can interact with structures such as the CNS, thus modifying the blood-brain barrier's (BBB´s) and blood-cerebrospinal fluid barrier´s (BCSFB´s) function and inducing aseptic neuroinflammation. During neuroinflammation, the participation of glial cells (astrocytes, microglia, and oligodendrocytes) plays an important role. They release cytokines, chemokines, reactive oxygen species, nitrogen species, peptides, and even excitatory amino acids that lead to neuronal damage. The neurons undergo morphological and functional changes that could initiate functional alterations to neurodegenerative processes. The present work aims to explain these processes and the pathophysiological interactions involved in CNS damage in the absence of microbes or inflammatory cells.
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Encefalite , Doenças Neuroinflamatórias , Humanos , Inflamação/metabolismo , Encefalite/patologia , Microglia/metabolismo , Neurônios/metabolismoRESUMO
Tuberculosis (TB) of the central nervous system (CNS) presents high mortality due to brain damage and inflammation events. The formation and deposition of immune complexes (ICs) in the brain microvasculature during Mycobacterium tuberculosis (Mtb) infection are crucial for its pathobiology. The relevance of ICs to Mtb antigens in the pathogenesis of CNS-TB has been poorly explored. Here, we aimed to establish a murine experimental model of ICs-mediated brain vasculitis induced by cell wall antigens of Mtb. We administered a cell wall extract of the prototype pathogenic Mtb strain H37Rv to male BALB/c mice by subcutaneous and intravenous routes. Serum concentration and deposition of ICs onto blood vessels were determined by polyethylene glycol precipitation, ELISA, and immunofluorescence. Histopathological changes in the brain, lung, spleen, liver, and kidney were evaluated by hematoxylin and eosin staining. Our results evidenced that vasculitis developed in the studied tissues. High serum levels of ICs and vascular deposition were evident in the brain, lung, and kidneys early after the last cell wall antigen administration. Cell wall Mtb antigens induce strong type III hypersensitivity reactions and the development of systemic vasculitis with brain vascular changes and meningitis, supporting a role for ICs in the pathogenesis of TB.
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Mycobacterium tuberculosis , Tuberculose , Vasculite , Masculino , Animais , Camundongos , Complexo Antígeno-Anticorpo , Modelos Animais de Doenças , Tuberculose/microbiologia , Antígenos de Bactérias , Parede CelularRESUMO
Central nervous system (CNS) tuberculosis is the most lethal and devastating form among the diseases caused by Mycobacterium tuberculosis. The mechanisms by which M. tuberculosis bacilli enter the CNS are still unclear. However, the BBB and the BCSFB have been proposed as possible routes of access into the brain. We previously reported that certain strains of M. tuberculosis possess an enhanced ability to cause secondary CNS infection in a mouse model of progressive pulmonary tuberculosis. Here, we evaluated the morphostructural and molecular integrity of CNS barriers. For this purpose, we analyzed through transmission electron microscopy the ultrastructure of brain parenchymal microvessels and choroid plexus epithelium from animals infected with two mycobacterial strains. Additionally, we determined the expression of junctional proteins and cytokines by immunological techniques. The results showed that the presence of M. tuberculosis induced disruption of the BCSFB but no disruption of the BBB, and that the severity of such damage was related to the strain used, suggesting that variations in the ability to cause CNS disease among distinct strains of bacteria may also be linked to their capacity to cause direct or indirect disruption of these barriers. Understanding the pathophysiological mechanisms involved in CNS tuberculosis may facilitate the establishment of new biomarkers and therapeutic targets.
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Doenças do Sistema Nervoso Central , Tuberculose Meníngea , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo , Doenças do Sistema Nervoso Central/metabolismo , Epitélio , CamundongosRESUMO
The differentiation between influenza and coronavirus disease 2019 (COVID-19) could constitute a diagnostic challenge during the ongoing winter owing to their clinical similitude. Thus, novel biomarkers are required to enable making this distinction. Here, we evaluated whether the surfactant protein D (SP-D), a collectin produced at the alveolar epithelium with known immune properties, was useful to differentiate pandemic influenza A(H1N1) from COVID-19 in critically ill patients. Our results revealed high serum SP-D levels in patients with severe pandemic influenza but not those with COVID-19. This finding was validated in a separate cohort of mechanically ventilated patients with COVID-19 who also showed low plasma SP-D levels. However, plasma SP-D levels did not distinguish seasonal influenza from COVID-19 in mild-to-moderate disease. Finally, we found that high serum SP-D levels were associated with death and renal failure among severe pandemic influenza cases. Thus, our studies have identified SP-D as a unique biomarker expressed during severe pandemic influenza but not COVID-19.
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COVID-19/genética , Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/genética , Proteína D Associada a Surfactante Pulmonar/genética , SARS-CoV-2 , Adulto , Idoso , Biomarcadores , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/virologia , Coinfecção , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Influenza Humana/diagnóstico , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteína D Associada a Surfactante Pulmonar/sangue , Índice de Gravidade de Doença , Avaliação de Sintomas , Adulto JovemRESUMO
BACKGROUND: Cellular immune responses are not well characterized during the initial days of acute symptomatic influenza infection. METHODS: We developed a prospective cohort of human subjects with confirmed influenza illness of varying severity who presented within a week after symptom onset. We characterized lymphocyte and monocyte populations as well as antigen-specific CD8+ T-cell and B-cell responses from peripheral blood mononuclear cells using flow cytometry and enzyme-linked immunospot assays. RESULTS: We recruited 68 influenza-infected individuals on average 3.5 days after the onset of symptoms. Three patients required mechanical ventilation. Influenza-specific CD8+ T-cell responses expanded before the appearance of plasmablast B cells. However, the influenza-specific CD8+ T-cell response was lower in infected subjects than responses seen in uninfected control subjects. Circulating populations of inflammatory monocytes were increased in most subjects compared with healthy controls. Inflammatory monocytes were significantly reduced in the 3 subjects requiring mechanical ventilation. Inflammatory monocytes were also reduced in a separate validation cohort of mechanically ventilated patients. CONCLUSIONS: Antigen-specific CD8+ T cells respond early during acute influenza infection at magnitudes that are lower than responses seen in uninfected individuals. Circulating inflammatory monocytes increase during acute illness and low absolute numbers are associated with very severe disease.
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Linfócitos T CD8-Positivos/patologia , Imunidade Celular , Influenza Humana/sangue , Influenza Humana/patologia , Adulto , Idoso , Feminino , Humanos , Influenza Humana/imunologia , Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Estudos Prospectivos , Respiração Artificial , Índice de Gravidade de DoençaRESUMO
Specific spatial organization of granulomas within the lungs is crucial for protective anti-tuberculosis (TB) immune responses. However, only large animal models such as macaques are thought to reproduce the morphological hallmarks of human TB granulomas. In this study, we show that infection of mice with clinical "hypervirulent" Mycobacterium tuberculosis (Mtb) HN878 induces human-like granulomas composed of bacilli-loaded macrophages surrounded by lymphocytes and organized localization of germinal centers and B-cell follicles. Infection with laboratory-adapted Mtb H37Rv resulted in granulomas that are characterized by unorganized clusters of macrophages scattered between lymphocytes. An in-depth exploration of the functions of B cells within these follicles suggested diverse roles and the activation of signaling pathways associated with antigen presentation and immune cell recruitment. These findings support the use of clinical Mtb HN878 strain for infection in mice as an appropriate model to study immune parameters associated with human TB granulomas.
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Linfócitos B/fisiologia , Granuloma/microbiologia , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/microbiologia , Animais , Granuloma/patologia , Cadeias mu de Imunoglobulina/genética , Cadeias mu de Imunoglobulina/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Linfócitos/fisiologia , Macaca mulatta , Macrófagos/fisiologia , Camundongos Knockout , Tuberculose Pulmonar/patologia , VirulênciaRESUMO
BACKGROUND: Little is known about the clinical phenotype of amyotrophic lateral sclerosis (ALS) in non-Caucasian populations. Here, we aimed to describe the clinical characteristics, prognostic factors and survival of Mexican patients with ALS. METHODS: We conducted a retrospective study by reviewing the medical records of patients with ALS that attended and were regularly followed at a third level hospital in Mexico City from 2000 to 2015. We calculated absolute and relative frequencies of the clinical characteristics from all the participants. We also estimated correlation coefficients between clinical features and overall survival. Additionally, survival rates were compared for all participants grouped according to different clinical features using the Kaplan-Meier method and the log-rank test. RESULTS: We enrolled 45 ALS patients, 53.33% had spinal-onset ALS and 46.66% presented bulbar ALS. The male/female ratio was 0.8. The mean age at onset of symptoms was 58.11 years. Mean survival time from onset was 64.73 ± 34.83 months. Cumulative survival rate after 5 years of disease onset was 44.44%. Age at onset and age at diagnosis inversely correlated with overall survival time. Also, we found that bulbar-onset, short diagnostic delay, percutaneous endoscopic gastrostomy, mechanical ventilation, and lower total cholesterol serum levels were associated with short survival. CONCLUSIONS: The clinical characteristics of Mexican ALS patients differ from the disease phenotype observed in Caucasians. Nonetheless, the predictive value of certain well-recognized prognostic factors remains consistent in our population. The current study provides relevant information for a better understanding of prognostic factors in ALS patients from Mexico and other Latin American countries.
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Esclerose Lateral Amiotrófica/mortalidade , Adulto , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Introduction: The proteolytic activity of A Disintegrin and Metalloproteinase 17 (ADAM17) regulates the release of tumor necrosis factor (TNF) and TNF receptors (TNFRs) from cell surfaces. These molecules play important roles in tuberculosis (TB) shaping innate immune reactions and granuloma formation. Methods: Here, we investigated whether single nucleotide polymorphisms (SNPs) of ADAM17 influence TNF and TNFRs levels in 224 patients with active TB (ATB) and 118 healthy close contacts. Also, we looked for significant associations between SNPs of ADAM17 and ATB status. TNF, TNFR1, and TNFR2 levels were measured in plasma samples by ELISA. Four SNPs of ADAM17 (rs12692386, rs1524668, rs11684747, and rs55790676) were analyzed in DNA isolated from peripheral blood leucocytes. The association between ATB status, genotype, and cytokines was analyzed by multiple regression models. Results: Our results showed a higher frequency of rs11684747 and rs55790676 in close contacts than ATB patients. Coincidentally, heterozygous to these SNPs of ADAM17 showed higher plasma levels of TNF compared to homozygous to their respective ancestral alleles. Strikingly, the levels of TNF and TNFRs distinguished participant groups, with ATB patients displaying lower TNF and higher TNFR1/TNFR2 levels compared to their close contacts. Conclusion: These findings suggest a role for SNPs of ADAM17 in genetic susceptibility to ATB.
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BACKGROUND: Limited literature exists regarding the differences in demographics, causes, comorbidities, presentation, and structural changes associated with cervical spine degeneration in patients from distinct geographic regions. The authors aimed to evaluate the demographic and clinical characteristics of patients with cervical spine degeneration admitted to a single center in Mexico. METHODS: This study enrolled patients with degenerative disease of the cervical spine. Clinical data were retrieved from medical records and retrospectively characterized. RESULTS: A total of 50 patients with cervical spine degeneration were included in the analysis. Of these, 26% were men with a median age of 54 years. Hypertension, depression, anxiety, obesity, and alcohol consumption were presented in about a quarter of the participants. In addition, we observed hypertriglyceridemia and hypercholesterolemia in 72% and 46% of participants, respectively. The median duration of symptoms was 11 months, including radicular arm/neck pain (80%), tingling (80%), reduced muscle strength (48%), and gait disturbances (48%). Forty percent of patients had 2 cervical segments radiologically involved, mainly at C5-C6, with changes such as disc herniation (88%), foraminal stenosis with nerve root compression (67%), reduced spinal canal-to-vertebral body ratio (38%), and ligamentum flavum hypertrophy (24%). Also, 22% of patients showed degenerative cervical myelopathy. Strikingly, 48% of enrolled individuals showed cervicolumbar tandem spinal stenosis, mainly in L4-L5 and L5-S1, who were generally older, had a longer duration of symptoms, and had a higher comorbidity burden, including hyperglycemia, hypertension, and depression. CONCLUSIONS: The demographic and clinical characteristics of degenerative cervical spine disease in Mexico differ with respect to other geographical regions by a younger age of diagnosis, a high frequency of cardiovascular, metabolic, and mental health comorbidities, and an increased prevalence of concomitant lumbar spinal stenosis. CLINICAL RELEVANCE: Our findings reveal a considerably high burden of cervicolumbar tandem spinal stenosis as a distinctive feature of Mexican patients with cervical spine degeneration.
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INTRODUCTION: Central nervous system (CNS) tuberculosis (TB) is the most severe form of TB due to its high mortality and functional sequelae. There are several differential diagnoses for TB; and, it can also cause secondary conditions, such as vasculitis. METHODOLOGY: 155 biopsies, corresponding to 155 different patients out of 5,386 registered biopsies from 2008-2013, met the criteria of unknown etiology vasculitis and evidence of cerebral vascular disease. These were analyzed to assess the presence of central nervous system TB. The selected cases were assessed with Suzaan Marais (SM) criteria for clinical tuberculosis. After that, Ziehl-Neelsen (ZN) staining and polymerase chain reaction (PCR) were performed to amplify a fragment of the insertion sequence IS6110 of M. tuberculosis. 21 patients met the criteria for definitive tuberculosis by ZN staining and PCR, and 2 met the criteria for possible tuberculosis. Tumor necrosis factor (TNF)-α, TNF-R1, and TNF-R2 were determined by immunohistochemistry in histological sections from formalin-fixed paraffin-embedded (FF-PE) tissues in the 23 selected patients. RESULTS: Granulomatous TB was present in almost half of the cases. TNF-R1 and TNF-R2 were expressed mainly in blood vessels, histiocytes, and macrophages. TNF-R2 expression was higher than the other markers, which suggests an anti-inflammatory response against M. tuberculosis. CONCLUSIONS: The histopathological presentation of TB is not always limited to granulomas, abscesses, or meningitis; there are also clinical presentations characterized only with chronic inflammation of nervous and vascular tissue.
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Mycobacterium tuberculosis , Tuberculose , Vasculite , Humanos , Receptores Tipo I de Fatores de Necrose Tumoral , Receptores Tipo II do Fator de Necrose Tumoral , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa , Vasculite/complicaçõesRESUMO
In this model we use a dynamic and multistable Boolean regulatory network to provide a mechanistic explanation of the lymphopenia and dysregulation of CD4+ T cell subsets in COVID-19 and provide therapeutic targets. Using a previous model, the cytokine micro-environments found in mild, moderate, and severe COVID-19 with and without TGF-ß and IL-10 was we simulated. It shows that as the severity of the disease increases, the number of antiviral Th1 cells decreases, while the the number of Th1-like regulatory and exhausted cells and the proportion between Th1 and Th1R cells increases. The addition of the regulatory cytokines TFG-ß and IL-10 makes the Th1 attractor unstable and favors the Th17 and regulatory subsets. This is associated with the contradictory signals in the micro-environment that activate SOCS proteins that block the signaling pathways. Furthermore, it determined four possible therapeutic targets that increase the Th1 compartment in severe COVID-19: the activation of the IFN-γ pathway, or the inhibition of TGF-ß or IL-10 pathways or SOCS1 protein; from these, inhibiting SOCS1 has the lowest number of predicted collateral effects. Finally, a tool is provided that allows simulations of specific cytokine environments and predictions of CD4 T cell subsets and possible interventions, as well as associated secondary effects.
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BACKGROUND: Nasal chondromesenchymal hamartomas (NCMHs) are benign, slow-growing lesions formed by mesenchymal and cartilaginous components. They occur predominantly in male infants at the nasopharynx and orbit. Rare cases have been reported in adults. Ectopic NCMHs occurring in other head regions without the typical nasopharyngeal or orbital involvement have not been previously described. OBSERVATIONS: The authors presented the case of a 40-year-old woman with a giant mass in the left frontoparietal region that started to enlarge progressively after the patient's first pregnancy at the age of 21 years. The tumor caused intense headaches, nausea, vomiting, asthenia, and syncope. On admission, the neurological examination revealed no abnormalities. Brain magnetic resonance imaging showed a solid homogeneous tumor without intraaxial involvement extending inferiorly to the left zygomatic arch, with a significant mass effect on the adjacent bones but no infiltration. Remarkably, digital subtraction angiography demonstrated that the tumor received blood supply from superficial as well as intracranial branches of the left vertebral artery. After tumor resection, histopathological analysis revealed characteristics indistinguishable from an NCMH. LESSONS: The authors described a rare NCMH of the scalp with intracranial blood supply in an adult patient. A case with similar characteristics had not been reported before.
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Emerging respiratory viruses are major health threats due to their potential to cause massive outbreaks. Over the past 2 years, the coronavirus disease 2019 (COVID-19) pandemic has caused millions of cases of severe infection and deaths worldwide. Although natural and vaccine-induced protective immune mechanisms against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been increasingly identified, the factors that determine morbimortality are less clear. Comparing the immune signatures of COVID-19 and other severe respiratory infections such as the pandemic influenza might help dissipate current controversies about the origin of their severe manifestations. As such, identifying homologies in the immunopathology of both diseases could provide targets for immunotherapy directed to block shared pathogenic mechanisms. Meanwhile, finding unique characteristics that differentiate each infection could shed light on specific immune alterations exploitable for diagnostic and individualized therapeutics for each case. In this study, we summarize immunopathological aspects of COVID-19 and pandemic influenza from the perspective of cytokine storms as the driving force underlying morbidity. Thereby, we analyze similarities and differences in the cytokine profiles of both infections, aiming to bring forward those molecules more attractive for translational medicine and drug development.
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COVID-19 , Influenza Humana , Síndrome da Liberação de Citocina , Humanos , Influenza Humana/epidemiologia , Influenza Humana/terapia , Pandemias , SARS-CoV-2RESUMO
The costs of coronavirus disease 2019 (COVID-19) are devastating. With millions of deaths worldwide, specific serological biomarkers, antiviral agents, and novel therapies are urgently required to reduce the disease burden. For these purposes, a profound understanding of the pathobiology of COVID-19 is mandatory. Notably, the study of immunity against other respiratory infections has generated reference knowledge to comprehend the paradox of the COVID-19 pathogenesis. Past studies point to a complex interplay between cytokines and other factors mediating wound healing and extracellular matrix (ECM) remodeling that results in exacerbated inflammation, tissue injury, severe manifestations, and a sequela of respiratory infections. This review provides an overview of the immunological process elicited after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Also, we analyzed available data about the participation of matrix metalloproteinases (MMPs) and transforming growth factor-beta (TGF-ß) in immune responses of the lungs. Furthermore, we discuss their possible implications in severe COVID-19 and sequela, including pulmonary fibrosis, and remark on the potential of these molecules as biomarkers for diagnosis, prognosis, and treatment of convalescent COVID-19 patients. Our review provides a theoretical framework for future research aimed to discover molecular hallmarks that, combined with clinical features, could serve as therapeutic targets and reliable biomarkers of the different clinical forms of COVID-19, including convalescence.
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COVID-19 , Metaloproteinases da Matriz , Fator de Crescimento Transformador beta , Biomarcadores , COVID-19/imunologia , Efeitos Psicossociais da Doença , Humanos , Metaloproteinases da Matriz/imunologia , SARS-CoV-2 , Fator de Crescimento Transformador beta/imunologiaRESUMO
Mycobacterium tuberculosis (Mtb) infects 25% of the world's population and causes tuberculosis (TB), which is a leading cause of death globally. A clear understanding of the dynamics of immune response at the cellular level is crucial to design better strategies to control TB. We use the single-cell RNA sequencing approach on lung lymphocytes derived from healthy and Mtb-infected mice. Our results show the enrichment of the type I IFN signature among the lymphoid cell clusters, as well as heat shock responses in natural killer (NK) cells from Mtb-infected mice lungs. We identify Ly6A as a lymphoid cell activation marker and validate its upregulation in activated lymphoid cells following infection. The cross-analysis of the type I IFN signature in human TB-infected peripheral blood samples further validates our results. These findings contribute toward understanding and characterizing the transcriptional parameters at a single-cell depth in a highly relevant and reproducible mouse model of TB.
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Mycobacterium tuberculosis , Tuberculose , Animais , Imunidade , Células Matadoras Naturais , Pulmão/metabolismo , Camundongos , Tuberculose/metabolismoRESUMO
Interferon-induced transmembrane (IFITM) proteins mediate protection against enveloped viruses by blocking membrane fusion at endosomes. IFITM1 and IFITM3 are crucial for protection against influenza, and various single nucleotide polymorphisms altering their function have been linked to disease susceptibility. However, bulk IFITM1 and IFITM3 mRNA expression dynamics and their correlation with clinical outcomes have not been extensively addressed in patients with respiratory infections. In this study, we evaluated the expression of IFITM1 and IFITM3 in peripheral leukocytes from healthy controls and individuals with severe pandemic influenza A(H1N1) or coronavirus disease 2019 (COVID-19). Comparisons between participants grouped according to their clinical characteristics, underlying disease, and outcomes showed that the downregulation of IFITM1 was a distinctive characteristic of severe pandemic influenza A(H1N1) that correlated with outcomes, including mortality. Conversely, increased IFITM3 expression was a common feature of severe pandemic influenza A(H1N1) and COVID-19. Using a high-dose murine model of infection, we confirmed not only the downregulation of IFITM1 but also of IFITM3 in the lungs of mice with severe influenza, as opposed to humans. Analyses in the comparative cohort also indicate the possible participation of IFITM3 in COVID-19. Our results add to the evidence supporting a protective function of IFITM proteins against viral respiratory infections in humans.