Details

Autor(en) / Beteiligte

• Oliveira, Fabrício M.S.
• Kraemer, Lucas
• Vieira-Santos, Flaviane
• Leal-Silva, Thaís
• Gazzinelli-Guimarães, Ana C.
• Lopes, Camila A.
• Amorim, Chiara C.O.
• Pinheiro, Guilherme R.G.
• Moura, Matheus S.
• Matias, Pablo H.P.
• Barbosa, Fernando S.
• Caliari, Marcelo V.
• Weatherhead, Jill E.
• Bueno, Lilian L.
• Russo, Remo C.
• Fujiwara, Ricardo T.

Titel

The long-lasting Ascaris suum antigens in the lungs shapes the tissue adaptation modifying the pulmonary architecture and immune response after infection in mice

Ist Teil von

• Microbial pathogenesis, 2024-01, Vol.186, p.106483-106483, Article 106483

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Ascariasis is the most prevalent helminth affecting approximately 819 million people worldwide. The acute phase of Ascariasis is characterized by larval migration of Ascaris spp., through the intestinal wall, carried to the liver and lungs of the host by the circulatory system. Most of the larvae subsequently transverse the lung parenchyma leading to tissue injury, reaching the airways and pharynx, where they can be expectorated and swallowed back to the gastrointestinal tract, where they develop into adult worms. However, some larvae are trapped in the lung parenchyma inciting an inflammatory response that causes persistent pulmonary tissue damage long after the resolution of infection, which returns to tissue homeostasis. However, the mechanism by which chronic lung disease develops and resolves remains unknown. Here, using immunohistochemistry, we demonstrate that small fragments and larval antigens of Ascaris suum are deposited and retained chronically in the lung parenchyma of mice following a single Ascaris infection. Our results reveal that the prolonged presence of Ascaris larval antigens in the lung parenchyma contributes to the persistent immune stimulation inducing histopathological changes observed chronically following infection, and clearly demonstrate that larval antigens are related to all phases of tissue adaptation after infection: lung injury, chronic inflammation, resolution, and tissue remodeling, in parallel to increased specific humoral immunity and the recovery of lung function in mice. Additional insight is needed into the mechanisms of Ascaris antigen to induce chronic immune responses and resolution in the host lungs following larval migration. A scenario of the lung tissue adaptation process induced by A. suum infection is illustrated according to different pulmonary physiological and immune hallmarks. The host initially infects by ingesting embryonated A. suum eggs, hatching in the intestine. Larval worms migrate into the lungs through the blood vessels, with the peak of alveolar space larval migration observed after 7 days of infection, causing lung injury, also related to alveolar hemorrhage and predominance of neutrophil influx, triggering acutely and mixed Th1 cytokine (IL-12), Th2 cytokines (IL-5 and IL-33) and tissue repair cytokines (IL-10 and TGF-β1), systemic IgE response specific anti-A. suum(A) and iBALT formation (C), with the worsening of pulmonary function (B). Afterward, the chronic inflammation persists 14 days after infection (that represents one week after the peak of lung larval migration and injury), in which there are no larvae or hemorrhage observed in the lungs, but still small larval fragments and antigens of A. suum dispersed in the parenchyma, that sustain a mixed leukocyte influx (neutrophils, eosinophils, macrophages, and lymphocytes), with pro-inflammatory cytokine (IL-1β), mixed Th2 cytokines (IL-4 and IL-33) and tissue repair (IL-10) cytokines, local in airways (IgA) and systemic (IgE/IgG3) humoral response specific anti-A. suum concomitant (A) with iBALT formation (C), but still worsening lung function (B). The resolution of inflammation is observed 42 days after infection (two weeks after the peak of lung larval migration and injury) with no hemorrhage, larvae, or small larval fragments in the lungs. However, A. suum antigens are found within macrophages, with signs of resolution of inflammation characterized by a reduction in the inflammatory infiltrate, but increased macrophages, and a mixed pro-inflammatory (IL-1β), Th1 (IL-12), Th2 (IL-33), and tissue repair (IL-10) cytokines, with increased locally in airways (IgA) and systemic (IgE/IgG1/IgG3) humoral response specific anti-A. suum(A) concomitant with iBALT (C), also with an improvement in lung function (B). After 70 days of infection is characterized by tissue remodeling, in which A. suum antigens are observed only inside of some macrophages and, but with reduction of the alveolar thickening with the reversion of pulmonary dysfunction (days 7 and 14), also related to a reduction in inflammatory infiltrate as a consequence of continuing resolution and tissue healing (A). Despite the transient dysfunction during injury and chronic inflammatory phases, pulmonary physiological functions are returned during the transition of tissue remodeling to homeostasis (B). However, the A. suum infection triggers an “immune scar” as a memory of a previous immune response after 70 days of infection, leading to an immunological tissue adaptation (A), marked by chronic iBALT persistence (C), mixed production of Th1 (IFN-γ and IL-12), Th2 (IL-4 and IL-5) and Th17 (IL-6 and IL-17A) cytokines in lungs, and a strong local in airways (IgA) and systemic (IgE, IgG1, IgG3) humoral response specific anti-A. suum(A), which are essential to control secondary infection. After 100 days of infection, the lungs may return to their homeostasis condition with tissue healing with immune memory.Panel A) Evolution of lung tissue adaptation in response to A. suum infection in mice, characterizing A. suum and antigens dispersion in lung tissue, leukocyte infiltration, cytokine levels, and humoral response along the time-points 7, 14, 42, and 70 days after A. suum infection, defining the phases of tissue injury, chronic inflammation, resolution of inflammation and tissue remodeling and healing, respectively.Panel B) Pulmonary dysfunction (left: Pressure-Volume curve; right: Flow-Volume curve) along the time-points in response to A. suum infection in mice depicting the tissue injury (7d), chronic inflammation (14d), resolution of inflammation (42d), and tissue remodeling and healing (70d) phases.Panel C) Evolution of tissue pathology and iBALT formation in response to A. suum infection in mice along the time-points of tissue injury (7d), chronic inflammation (14d), resolution of inflammation (42d), and tissue remodeling and healing (70d) phases. [Display omitted] •Single infection with A. suum causes long-term histopathological changes.•Macrophages with A. suum antigens at late stages contribute to immune system activation.•Immunohistochemistry used for the first time to identify ascaris antigens.