MAV_4644 Interaction with the Host Cathepsin Z Protects Mycobacterium avium subsp. hominissuis from Rapid Macrophage Killing
Related Experiment Video
Updated: Jan 24, 2026
Intradermal Inoculation of Mycobacterium avium in the Mouse Ear
Published on: July 3, 2025
Matthew S Lewis1, Lia Danelishvili2, Sasha J Rose3
1Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA. Matthew.lewis@oregonstate.edu.
Abstract:
Mycobacterium avium subspecies hominissuis (MAH) is an opportunistic pathogen that is ubiquitous in the environment and often isolated from faucets and showerheads. MAH mostly infects humans with an underlying disease, such as chronic pulmonary disorder, cystic fibrosis, or individuals that are immunocompromised. In recent years, MAH infections in patients without concurrent disease are increasing in prevalence as well. This pathogen is resistant to many antibiotics due to the impermeability of its envelope and due to the phenotypic resistance established within the host macrophages, making difficult to treat MAH infections. By screening a MAH transposon library for mutants that are susceptible to killing by reactive nitrogen intermediaries, we identified the MAV_4644 (MAV_4644:Tn) gene knockout clone that was also significantly attenuated in growth within the host macrophages. Complementation of the mutant restored the wild-type phenotype. The MAV_4644 gene encodes a dual-function protein with a putative pore-forming function and ADP-ribosyltransferase activity. Protein binding assay suggests that MAV_4644 interacts with the host lysosomal peptidase cathepsin Z (CTSZ), a key regulator of the cell signaling and inflammation. Pathogenic mycobacteria have been shown to suppress the action of many cathepsins to establish their intracellular niche. Our results demonstrate that knocking-down the cathepsin Z in human macrophages rescues the attenuated phenotype of MAV_4644:Tn clone. Although, the purified cathepsin Z by itself does not have any killing effect on MAH, it contributes to bacterial killing in the presence of the nitric oxide (NO). Our data suggest that the cathepsin Z is involved in early macrophage killing of MAH, and the virulence factor MAV_4644 protects the pathogen from this process.
Insights
Mycobacterium avium subspecies hominissuis (MAH) infections are difficult to treat. A novel virulence factor, MAV_4644, protects MAH from macrophage killing by inhibiting cathepsin Z, a key component of the host
Area of Science:
- Microbiology
- Immunology
- Pathogenesis
Background:
- Mycobacterium avium subspecies hominissuis (MAH) is an opportunistic pathogen found in the environment, frequently causing infections in immunocompromised individuals.
- MAH infections are challenging to treat due to antibiotic resistance and intracellular survival mechanisms within macrophages.
- Emerging cases of MAH infections in immunocompetent individuals highlight the need to understand its virulence factors.
Purpose of the Study:
- To identify novel virulence factors of MAH involved in host-pathogen interactions.
- To elucidate the mechanism by which MAH survives within macrophages.
- To investigate the role of MAV_4644 in MAH pathogenesis and host defense.
Main Methods:
- Screening of a MAH transposon library to identify mutants susceptible to reactive nitrogen intermediates.
- Genetic manipulation (gene knockout and complementation) of MAV_4644 in MAH.
- Assessment of bacterial growth and survival within host macrophages.
- Protein binding assays to identify host targets of MAV_4644.
- Investigating the role of cathepsin Z in MAH-macrophage interactions.
Main Results:
- A MAV_4644 gene knockout mutant (MAV_4644:Tn) showed significant attenuation in growth within macrophages.
- MAV_4644 encodes a protein with dual function: pore-forming activity and ADP-ribosyltransferase activity.
- MAV_4644 interacts with the host lysosomal peptidase cathepsin Z (CTSZ).
- Knockdown of CTSZ in macrophages rescued the attenuated phenotype of the MAV_4644:Tn mutant.
- CTSZ contributes to bacterial killing in the presence of nitric oxide (NO), and MAV_4644 protects MAH from this process.
Conclusions:
- MAV_4644 is a novel virulence factor that facilitates MAH survival within macrophages.
- MAV_4644 inhibits the host innate immune response by targeting CTSZ, thereby preventing early macrophage-mediated killing of MAH.
- Understanding the MAV_4644-CTSZ interaction provides a potential target for novel therapeutic strategies against MAH infections.
Related Concept Videos
01:16Zones of Protection
Protective zones are defined by closed dashed lines, containing one or more components. A key characteristic of these zones is the strategic placement of...
02:31Protection of Alcohols
Protection
It defines a protecting group as the masking agent to make the more reactive species inert to a given set of conditions. This concept is depicted via the illustration of liquid flow through different outlets in an assembly of pipes. The analogy helps to understand the role...
01:27Protecting Self-Esteem
01:23Radial System Protection
In a radial system with a fault downstream of the third breaker, ideally, only the third breaker will open, isolating the fault and interrupting the load connected beyond it. The second breaker has a longer delay setting,...
02:39Predator-Prey Interactions
01:27Line Protection with Impedance Relays
Under normal conditions, low load currents keep the measured...