Harnessing Mycobacterium bovis BCG Trained Immunity to Control Human and Bovine Babesiosis

Babesiosis is a disease caused by tickborne hemoprotozoan apicomplexan parasites of the genus Babesia that negatively impacts public health and food security worldwide. Development of effective and sustainable vaccines against babesiosis is currently hindered in part by the absence of definitive host correlates of protection. Despite that, studies in Babesia microti and Babesia bovis, major causative agents of human and bovine babesiosis, respectively, suggest that early activation of innate immune responses is crucial for vertebrates to survive acute infection. Trained immunity (TI) is defined as the development of memory in vertebrate innate immune cells, allowing more efficient responses to subsequent specific and non-specific challenges. Considering that Mycobacterium bovis bacillus Calmette-Guerin (BCG), a widely used anti-tuberculosis attenuated vaccine, induces strong TI pro-inflammatory responses, we hypothesize that BCG TI may protect vertebrates against acute babesiosis. This premise is supported by early investigations demonstrating that BCG inoculation protects mice against experimental B. microti infection and recent observations that BCG vaccination decreases the severity of malaria in children infected with Plasmodium falciparum, a Babesia-related parasite. We also discuss the potential use of TI in conjunction with recombinant BCG vaccines expressing Babesia immunogens. In conclusion, by concentrating on human and bovine babesiosis, herein we intend to raise awareness of BCG TI as a strategy to efficiently control Babesia infection.

Trained Immunity-Based Vaccines: A Ready-to-Act Strategy to Tackle Viral Outbreaks

Viral outbreaks have become significant threats to global human public health. New emerging viruses, pathogen mutations, and even the progressive loss of efficacy in some existing vaccines are behind this problem, which is amplified by the rapid virus spread given the ease of current mobility. Taking into account that these outbreaks arise in the absence of conventional effective vaccines, alternative approaches based on trained (innate) immunity are being considered. This immunity is dependent on a functional reprogramming of innate immune cells, leading to an enhanced nonspecific response towards different pathogens, including viruses. Trained immunity-based vaccines (TIbVs), defined as vaccine formulations containing trained immunity inducers, could be used during viral outbreaks to confer non-specific protection but also to enhance adaptive specific immune responses. In this chapter, we aim to illustrate how TIbVs could tackle the above-mentioned situations derived from viral outbreaks, reviewing the potential of available TIbVs in such urgent situations with a special mention to COVID-19.

DNA Methylation Profiles of Immune Cells From Tuberculosis-Exposed Individuals Overlap With BCG-Induced Epigenetic Changes

The mechanism of protection of the only approved tuberculosis (TB) vaccine, Bacillus Calmette Guérin (BCG) is poorly understood. In recent years, epigenetic modifications induced by BCG have been demonstrated to reflect a state of trained immunity. The concept of trained immunity is now explored as a potential prevention strategy for a variety of infections. Studies on human TB immunity are dominated by those using peripheral blood as surrogate markers for immunity. Here, we instead studied the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters, and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to previously reported epigenetic changes and trained immunity in immune cells exposed to the BCG vaccine in human and animal studies. We further demonstrated that similar pathways were epigenetically modified in human macrophages trained with BCG in vitro. Altogether, our study demonstrates that similar epigenetic changes are induced by M. tuberculosis and BCG.

Transcriptome features of trained immunity in Drosophila

Immune memory is an ability of organisms to potentiate immune responses at secondary infection. Current studies have revealed that innate immunity, as well as adaptive immunity, exhibits the memory character called "trained immunity". Although it is suggested that epigenetic reprogramming plays important roles in trained immunity, its underlying mechanism is not fully understood, especially on the individual level. Here we established experimental systems for detecting trained immunity in Drosophila melanogaster. Namely, training infection with low-pathogenic bacteria enhanced the survival rate of the flies at subsequent challenge infection with high-pathogenic bacteria. We found that among low-pathogenic bacteria, Micrococcus luteus (Ml) and Salmonella typhimurium (St) mediated apparent training effects in fly, but seemed to act through different ways. Ml left training effects even after its removal from flies, while living St persisted inside flies for a long time. Our RNA-Seq analysis revealed that Ml-training enhanced the expression of immune-related genes during the challenge infection, but did not do so without challenge infection. In contrast, St-training maintained high expression of the immune-related genes with or without challenge. These results suggest that training effects with Ml and St were due to memory and persistence of immune responses, respectively. Furthermore, we searched the factor involved in Ml-training and identified a candidate, Ada2b, which is a component of the histone modification complex. We found that the Ada2b RNAi and mutant flies showed dampened enhancement of survival rates after Ml-training. These results suggest that Ada2b is involved in the Drosophila trained immunity.