The many uses of autophagosomes

Autophagy, in particular macroautophagy, is one of the host cell’s responses to microbial invasion.^1,2 Microbes that have entered the host cytosol may be sequestered within an autophagosome, which subsequently fuses with a lysosome, resulting in the death of the pathogen (Fig. 1A). Some pathogens, however, recognize that autophagosomes are a rich source of nutrition. This could be a major motive for certain pathogens such as Anaplasma phagocytophilum to establish their replicative niches within these compartments (Fig. 1B). A. phagocytophilum, an obligate intracellular pathogen that causes human granulocytic anaplasmosis, resides within a membrane-enclosed inclusion (which may derive from an endosome that is blocked in its maturation), and secretes Ats-1 through its type IV secretion system into the host cell. As described in a punctum in this issue of the journal, Ats-1 binds BECN1 and ATG14, stimulating autophagosome formation.³ Autophagosomes fuse with the A. phagocytophilum inclusion membrane, yet lysosomes do not. If indeed autophagosomes are a source for nutrition, then how would A. phagocytophilum digest its food without lysosomal hydrolases? The authors propose that A. phagocytophilum accomplishes this through its own surface-associated proteases. Thus, it seems that this pathogen recruits nutrient-rich autophagosomes to the inclusion membranes as a food source, then generates amino acids from the cytosolic cargo using its own proteases.

Legionella pneumophila promotes sequestration by autophagosomes via a type IV secreted molecule called legA9, yet delays maturation into autolysosomes.⁴ Why would a bacterium initiate macroautophagy and sequestration only to delay fusion with the lysosome? Why did the pathogen not develop a mechanism to avoid autophagy altogether? It seems that transit through the autophagic pathway makes certain organisms such as L. pneumophila suited for intravacuolar survival and multiplication (Fig. 1C). A similar mechanism is used by Coxiella burnetii.⁵

Burkholderia cenocepacia actively suppresses the expression of macroautophagy molecules in wild-type and cystic fibrosis-derived macrophages. Thus, in wild-type macrophages, it delays autophagosome fusion with the lysosomes. This strategy goes even further in cystic fibrosis (CF)-derived macrophages, as B. cenocepacia avoids autophagy altogether, since autophagy is already impaired in CF macrophages (Fig. 1D).⁶ This predisposes CF patients to B. cenocepacia infection and also to Pseudomonas aeruginosa that is typically cleared by autophagy in healthy wild-type cells.⁷

Organisms such as Helicobacter pylori are more confusing. It appears that H. pylori interacts with autophagosomes differentially according to the host cell line and bacterial strain (see ref. 8, which is in this issue of the journal). Thus, it is still difficult to describe a specific strategy for how H. pylori interacts with the autophagy system.

Some pathogens such as Group A Streptococcus (GAS) can escape their enclosing vacuole, enter the cytoplasm, and become captured by autophagosomes that fuse to become larger.⁹ Subsequent fusion with lysosomes causes the death of most intracellular GAS. Francisella tularensis also re-enters the endocytic pathway via autophagy after cytoplasmic replication (Fig. 1E).¹⁰ Thus, autophagy is also an additional defense barrier against pathogens that penetrate the first defense of the endocytic pathway.

Therefore, depending on the microbe, an autophagosome can be a sanctuary, a food source, a replication niche, or a precursor to death, reflecting an ongoing battle between the host and the pathogen for an evolutionary advantage.