Researchers from Brazil, the United States, New Zealand, and Argentina presented new findings on trained immunity, host-directed therapies, antiviral responses, and cellular mechanisms associated with inflammation and neurodegeneration.
How do past infections influence the body’s response to new pathogens? How can innate immunity be stimulated to fight infectious diseases and even cancer? These were some of the questions discussed on Friday afternoon (September 4), during the first day of the International Symposium on Innate Immunity, held at the University of São Paulo (USP). Organized by the University of São Paulo’s Institute of Biomedical Sciences (ICB-USP) and the Institut Pasteur de São Paulo (IPSP), with support from the São Paulo Research Foundation (FAPESP), the event brought together Brazilian and international researchers to discuss recent advances in the study of innate immunity.
The afternoon program highlighted research on immune protection induced by previous infections, new therapeutic strategies for tuberculosis, the influence of prior inflammatory processes on respiratory infections, and cellular mechanisms involved in neuroinflammatory diseases.
Trained immunity and protection beyond the original target
Opening the session, Alan Sher, from the National Institutes of Health (NIH), presented a historical and conceptual analysis of immune protection mechanisms that extend beyond the specific target of an infection or vaccine. He discussed evidence that innate immunity can acquire long-lasting functional characteristics capable of broadening protection against different pathogens.
Reviewing decades of studies involving the BCG vaccine, Sher emphasized that the protection induced by certain immune stimuli depends on a complex interaction between innate and adaptive immunity.
According to Sher, evidence accumulated over recent decades shows that what is known as cross-protection cannot be explained simply by the isolated action of only one of the two arms of the immune system. He discussed models in which the activation of adaptive immunity can feed back into innate immune mechanisms and enhance responses against targets unrelated to the initial stimulus.
The researcher also presented studies identifying interferon gamma (IFN-γ) as an important stimulus for the priming and training of myeloid cells and discussed the potential role of bone marrow in these mechanisms.
Trained immunity involves the functional reprogramming of innate immune cells, including epigenetic changes capable of modifying the intensity of responses to subsequent challenges. Sher emphasized, however, that trained immunity and cross-protection should not be considered synonymous. Although the two phenomena are related, evidence still indicates that mechanisms of protection beyond the original target may occur without depending exclusively on classical trained immunity.
New strategy seeks to strengthen the host response against tuberculosis
Diego Costa, from the University of São Paulo, then presented findings exploring a different approach to tuberculosis treatment. Instead of acting directly on the bacterium Mycobacterium tuberculosis, the research seeks to enhance the body’s natural defense mechanisms.
The research focuses on the signaling pathway formed by the GAS6 protein and the AXL and MERTK receptors, which are involved in the recognition and removal of apoptotic cells by macrophages. According to Costa, experiments in animal models showed that the administration of GAS6 reduced the bacterial burden and the area of inflamed lung tissue. In cellular experiments, the treatment also increased efferocytosis—the process through which macrophages remove apoptotic cells—and improved control of bacterial replication.
Costa emphasized that host-directed therapies are not intended to replace antibiotic treatment for tuberculosis but to complement it by strengthening defense mechanisms or reducing harmful inflammatory responses. The findings presented suggest that modulating this pathway could represent a new host-directed therapeutic approach to tuberculosis.
The immune legacy of infections
Kerry Hilligan, from the Malaghan Institute of Medical Research in New Zealand, discussed how previous infections and inflammatory processes can leave long-lasting changes in the lung microenvironment and influence responses to future respiratory infections.
Using different experimental models, the group demonstrated that distinct types of inflammation leave long-lasting immune marks in lung tissue. The examples presented included studies involving BCG, helminth infections, and fungal infections.
The findings showed that different previous inflammatory experiences can promote resistance to viral infections through distinct mechanisms. In the model involving intravenously administered BCG, protection against SARS-CoV-2 was associated with the action of IFN-γ on non-hematopoietic lung cells, including the respiratory epithelium. Animals previously infected with helminths exhibited more efficient recruitment of virus-specific CD8 T cells, accompanied by a faster reduction in viral burden in the lungs. Following a previous fungal infection, the animals showed greater survival and better-preserved lungs, even without an equivalent reduction in viral burden, suggesting less severe immunopathology.
Taken together, the findings indicate that the lungs can retain a type of “memory” of previous inflammatory experiences, capable of changing how the body responds to new infectious challenges. According to the researcher, understanding these effects could open new possibilities for harnessing these responses in future host-protection strategies.
Dendritic cell diversity broadens the understanding of immune responses
The heterogeneity of dendritic cells was the subject of a presentation by Fernando Sulczewski, from USP. He discussed how recent advances in single-cell sequencing and cellular characterization techniques have revealed far greater diversity among these cells than previously thought. The presentation focused on the characterization of transitional dendritic cells (tDCs), a recently identified cell population with characteristics intermediate between different classical groups of dendritic cells.
The studies presented indicate that these cells have a distinct molecular signature and a defined developmental trajectory, sharing a bone marrow progenitor with plasmacytoid dendritic cells. The findings also suggest that tDCs participate in the modulation of inflammatory responses during viral infections. Data presented during the talk further indicated that these cells may constitute an important source of IL-1β in response to viral infection, contributing to systemic inflammatory processes.
The findings also demonstrate how new technologies are leading researchers to revise the traditional classification of dendritic cells by identifying new populations, cellular origins, and functions. Sulczewski also presented results investigating how malaria affects the development of these cells in the bone marrow. In the models studied, infection caused a reduction in different dendritic cell populations and their bone marrow progenitors, indicating that the disease alters the developmental process of these cells.
Intestinal defense depends on cooperation between innate and adaptive immunity
Leandro Araújo, from USP, discussed the role of group 3 innate lymphoid cells (ILC3s) in protecting the intestine. Using an experimental model developed specifically to eliminate ILC3s while preserving the normal development of CD4 and CD8 T cells, the group demonstrated that ILC3s play an essential role in the initial response against intestinal bacterial infections.
The findings indicated that, in more severe infections, the absence of these cells seriously compromises host protection. In less severe infections, however, T lymphocytes that produce IL-17 and IL-22 can partially compensate for this deficiency. The data therefore point to a complementary relationship between the innate and adaptive components of mucosal immunity: ILC3s are particularly important during the early stages of the response, while T cells can take over part of this function as the infection progresses.
Brain inflammation and neuronal loss
The final presentation of the afternoon was delivered by Guillermo Giambartolomei, from the University of Buenos Aires, who discussed mechanisms through which microglial cells may contribute to neuronal death during neuroinflammatory processes.
The researcher presented evidence that neurons may be eliminated not through traditional cell-death processes but through phagocytosis by activated microglia, a phenomenon known as phagoptosis.
In the experiments presented, the phagocytosed neurons were alive and showed few signs of apoptosis or necrosis, indicating that phagocytosis was not simply a consequence of cell death but could itself be the cause of neuronal loss.
The studies showed that this process depends on the coordinated action of two distinct inflammatory pathways: IL-6 increases the phagocytic capacity of microglia but is not sufficient on its own to cause neuronal death. Type I interferon signaling, in turn, controls mechanisms associated with nitric oxide production, which contributes to neuronal stress.
The findings help demonstrate how different inflammatory mediators can regulate distinct microglial functions—such as the ability to phagocytose cells and the production of reactive molecules—and how the combination of these mechanisms may contribute to neuronal loss during neuroinflammatory processes. The researcher also noted that similar phenomena have been observed in other experimental models, including Zika virus infection, exposure to LPS, and studies related to Alzheimer’s disease, suggesting that this mechanism may have broad relevance across different contexts of neuroinflammation and neurodegeneration.