Significance: Tuberculosis (TB) granulomas represent sites of both bacterial containment and tissue pathology. Macrophage killing of Mycobacterium tuberculosis ( Mtb ) in granulomas to contain infection must be regulated to prevent collateral tissue damage. Nitric oxide synthase-2 (NOS2) and arginase-1 (Arg1), macrophage enzymes metabolizing l -arginine, play key roles in this process. NOS2 produces reactive nitrogen intermediates to kill Mtb , whereas Arg1 regulates NOS2 activity via substrate competition. Arg1 activity could predominate in hypoxic regions of granulomas where NOS2 activity likely is suboptimal. Here we show that Arg1 plays a central role in restricting bacterial growth and restraining tissue damage within granulomas in TB and other chronic inflammatory diseases. These findings point to the modulation of Arg1 activity as a potential host-directed therapy for TB.

Organoids are multicellular culture systems that replicate tissue architecture and function, and are increasingly used as models of viral, bacterial, and protozoan infections. Organoids have great potential to improve our current understanding of helminth interactions with their hosts and to replace or reduce the dependence on using animal models. In this review, we discuss the applicability of this technology to helminth infection research, including strategies of co-culture of helminths or their products with organoids and the challenges, advantages, and drawbacks of the use of organoids for these studies. We also explore how complementing organoid systems with other cell types and components may allow more complex models to be generated in the future to further investigate helminth-host interactions.

Whipworms are large metazoan parasites that inhabit multi-intracellular epithelial tunnels in the large intestine of their hosts, causing chronic disease in humans and other mammals. How first-stage larvae invade host epithelia and establish infection remains unclear. Here we investigate early infection events using both Trichuris muris infections of mice and murine caecaloids, the first in-vitro system for whipworm infection and organoid model for live helminths. We show that larvae degrade mucus layers to access epithelial cells. In early syncytial tunnels, larvae are completely intracellular, woven through multiple live dividing cells. Using single-cell RNA sequencing of infected mouse caecum, we reveal that progression of infection results in cell damage and an expansion of enterocytes expressing of Isg15, potentially instigating the host immune response to the whipworm and tissue repair. Our results unravel intestinal epithelium invasion by whipworms and reveal specific host-parasite interactions that allow the whipworm to establish its multi-intracellular niche.

Although hatching from eggs is fundamental for nematode biology it remains poorly understood. For animal-parasitic nematodes in particular, advancement has been slow since the 1980s. Understanding such a crucial life-cycle process would greatly improve the tractability of parasitic nematodes as experimental systems, advance fundamental knowledge, and enable translational research. Here, we review the role of eggs in the nematode life cycle and the current knowledge on the hatching cascade, including the different inducing and contributing factors, and highlight specific areas of the field that remain unknown. We examine how these knowledge gaps could be addressed and discuss their potential impact and application in nematode parasite research, treatment, and control.