Human pathogens are diverse (bacteria, viruses, parasites) and destructive. Controlling and killing them is a major goal of humanity, hindered by (among other things) the sophisticated arsenals that pathogens have acquired over millions of years of evolutionary arms races with us. So it follows that we are keen to learn more about pathogen weaponry. A fascinating new preprint presents a powerful new resource in this struggle, with this added angle: the authors seek to not only block pathogenic weapons, but also to harness them.
Here is how the authors introduce the weapons:
Pathogens express specialized gene products, known as effectors, to manipulate host molecular processes and establish conditions that are favorable for their survival and transmission. Many bacteria and eukaryotic parasites have evolved secretion systems that inject effector proteins into the host cell during infection, whereas viral effectors are mostly produced by the host ribosomes after viral entry. By interfacing directly with host cellular machinery, effector proteins modulate immune responses, alter signaling pathways, and hijack metabolic processes to create a conducive environment for the pathogen.
In other words, the weapons — effectors — are both fearsome and potentially informative. Unfortunately, the -ome of effectors is poorly characterized, and this is the problem the authors tackled. They first assembled the missing -ome, which they call the eORFeome (e = effector, ORFeome = collection of potential gene sequences) from existing (and constantly accumulating) genomic data. They then developed a high-throughput platform to systematically screen these potential genes for various biological activities. This vast effort revealed completely new functions for many pathogen genes, and completely new genes from the collection. The paper is an impressive achievement, and the new functions and genes are extremely interesting. Check it out right away!
Let’s come back, though, to the ways this resource can be used and the need that the work addressed. Here are the authors’ words, which illustrate scientific writing that is clear and compelling (italics are the theirs):
The fact that thousands of sequenced pathogen ORFs have not been characterized has far-reaching consequences for many fields, both scientific and societal. Pathogenic effector proteins target functions and pathways relevant to cell biology and human health, particularly to infection, inflammation, and cancer. Systematic functional characterization of these effectors could uncover novel host vulnerabilities and reveal potential therapeutic entry points, thus pre-emptively illuminating mechanisms by which emerging pathogens might manipulate human cells. Moreover, the effectors constitute a vast untapped resource in novel tools to modulate and perturb host cell processes, potentially via entirely novel targets and mechanisms of action. As evolutionarily optimized perturbagens, they might moreover be more effective in modulating cellular functions than more traditional perturbations such as knocking out or overexpressing human genes.
Systematic Discovery of Pathogen Effector Functions across Human Pathogens and Pathways
In bioRxiv, 17 November 2025
From the groups of Mikko Taipale at the University of Toronto and Alexander Stark at the Research Institute of Molecular Pathology (IMP).
Snippet by Stephen Matheson
Image credit: Figure 1 from Pachano et al. linked above (CC BY).