Purple cell with a cluster of green tubes
A lack of robust genetic tools has hindered experiments in human primary macrophages. Gutierrez’s team developed a novel human macrophage cell model to dissect the role that autophagy plays in curtailing Mycobacterium tuberculosis (false colored here in green).
Tony Fearns

Mycobacterium tuberculosis (Mtb) and the human immune system have been at war for centuries. In a study published in Nature Microbiology, researchers probed the genetic weapons used on both sides of the battle and revealed how host cells deploy autophagy as a first line of defense to prevent Mtb from gaining a foothold.1 

“Initial interactions are critical for disease outcomes, so understanding factors that drive pathogenic versus protective responses are really important,” said Robert Watson, a microbiologist at Texas A&M University who was not involved in the study. 

Infected macrophages engage two main autophagy pathways to package Mtb into phagosomes for removal, but the exact details of how they do this are unknown. Maximiliano Gutierrez, a cell biologist at The Francis Crick Institute, investigated two key genes, ATG7 and ATG14, to uncover the underlying mechanisms.

Gutierrez’s team infected macrophages generated from human induced pluripotent stem cells with Mtb. Using CRISPR-Cas9 tools, they deleted ATG7 or ATG14 from macrophages and observed increased Mtb replication in both cases, confirming that both genes are required to curtail the pathogen. 

Next, the researchers disarmed Mtb by deleting two defense genes. As expected, wild type cells and ATG7-deficient cells showed hindered Mtb replication. However, when they performed the same experiment in ATG14-deficient cells, the disarmed Mtb replicated successfully. 

This surprised Gutierrez. “We weren't expecting such a strong phenotype with ATG14 because there is still some [ATG7] autophagy operating in those cells.” In subsequent experiments, the authors found that ATG14 regulates the fusion of Mtb-containing phagosomes with lysosomes for disposal, thus identifying another mechanism by which autophagy restricts the pathogen’s escape into the cytosol. 

While the researchers observed these effects in vitro using human iPSCs, others reported mixed results using mouse models.2,3 “It will take the field still some time to sort out exactly why autophagy in myeloid cells in vivo is important for the bacterial control and inflammatory response,” said Jen Philips, a microbiologist at Washington University School of Medicine who was not involved in the study. 


  1. Aylan B, et al. Nat Microbiol. 2023;8:803-818.
  2. Golovkine G, et al. Nat Microbiol. 2023;8:819-832.
  3. Kinsella R, et al. PLoS Biol. 2023;21(6):e3002159.