Role of human Toll‐like receptors in naturally occurring influenza A infections

Abstract

BackgroundWe investigated the roles of Toll‐like receptors (TLRs) in naturally occurring influenza.MethodsA prospective, case – control study was conducted. Adults hospitalized with virologically confirmed influenza A infections (onset <48 hours, before treatment) were compared with age‐/gender‐matched controls. TLRs (2, 3, 4, 7, 8, 9) expression in monocytes and dendritic cells (DCs – total, myeloid, plasmacytoid) was quantitated using flow cytometry. Gene expression of RLRs (RIG‐1, MDA‐5) was evaluated using real‐time PCR. Concomitant signaling molecules expression, plasma cytokine/chemokine concentrations, and respiratory tract viral loads were measured. PBMCs were cultured and stimulated ex vivo with TLR‐specific ligands for cytokine responses.ResultsForty two patients with influenza (24 A/H3N2, 18 A/H1N1pdm09) and 20 controls were studied. Patients' mean age was 68 ± 16 years; 81% had respiratory/cardiovascular complications. There were increased cellular expressions of TLR9, TLR8, TLR3, and TLR7 during influenza; TLR2 and TLR4 were suppressed. Results were similar for both virus strains. Higher TLR expression levels at presentation significantly correlated with lower viral loads (Spearman's rho: −0·46 to −0·69 for TLR9, TLR8, and TLR3; P‐values <0·05). Multivariate regression models (adjusted for age, comorbidity, disease severity, time from onset) confirmed their independent associations. Increased signaling molecules (phospho‐MAPKs, IκB) and inflammatory cytokines (IL‐6, sTNFR‐1, CCL2/MCP‐1; CXCL10/IP‐10, IFN‐γ) correlated with increased TLR expression. RLRs were upregulated simultaneously. PBMCs of patients with influenza showed significant, dynamic changes in their cytokine responses upon TLR stimulation, compared with controls.ConclusionsOur results suggest that TLRs play an important role in early, innate viral inhibition in naturally occurring influenza. Inflammatory cytokine responses are concomitantly induced. These findings support investigation of TLR targeting as a novel intervention approach for prophylaxis against influenza.

IN VITRO INTERACTION OF INFLUENZA VIRUS A(H1N1)pdm09 WITH MONOCYTIC MACROPHAGES: INDIVIDUAL RESPONSES OF TLR7 AND RIG1 RECEPTOR GENES

“…Выбор стимули-руемого GM-CSF рецепторного гена может быть индивидуален. Различная индивидуальная чув-ствительность клеток крови доноров к вирусам гриппа А и препаратам интерферонов отмечается в ряде сообщений [4,5,6,19].…”

“…По данным литературы, в моноцитах кро-ви больных гриппом А наблюдается повы-шение уровней экспрессии рецепторов TLR3 и TLR7 и подавление экспрессии рецепторов TLR2 и TLR4 [19]. Видимо, стимуляция рецеп-торов TLR7 и RIG1 -сенсоров вирусных РНК характерна для активно протекающей гриппоз-ной инфекции.…”

“…Вирусы гриппа А на ранних стадиях инфекции стимулируют реакции TLR/RLR-врожденного и адаптивного иммунитета [19,21]. На клеточной мембране рецептор TLR4 и C-тип лектиновых ре-цепторов (MMR-манозный и MGL-галактозный) взаимодействуют с глипопротеинами оболочки -гемагглютинином (ГА) и нейраминидазой (NA) [22].…”

Avaliação da imunidade antiviral no lavado nasal de pacientes com imunodeficiência comum variável em vigência de rinossinusites virais

“…Esse achado é diferente de outros estudos que avaliaram soro e lavado nasal em indivíduos com adenovírus e influenza A, onde houve aumento da secreção (242,243) . Nos anexos é possível perceber também que, apesar de não podermos quantificar a expressão do gene CXCL9, esse gene foi expresso em alguns sujeitos do estudo durante o quadro de rinossinusite aguda.…”

“…Também dosamos a proteína da quimiocina CCL2, produzida por monócitos, Com relação à quantificação de citocinas e quimiocinas, observamos um aumento da secreção dessas proteínas durante a infecção aguda em relação à ausência de infecção, comportamento semelhante ao observado em estudos que avaliaram a secreção dessas citocinas e quimiocinas no soro e em lavados/aspirados nasais durante quadros de infecções respiratórias (242,243,(260)(261)(262) . (243) .…”