Specificity of Immunoglobulin Response to Nontuberculous Mycobacteria Infection in People with Cystic Fibrosis

Malcolm, Kenneth C.; Wheeler, Emily A.; Calhoun, Kara; Lenhart-Pendergrass, Patricia M.; Rysavy, N.; Poch, Katie R.; Caceres, Silvia M.; Saavedra, Milene T.; Nick, Jerry A.

doi:10.1128/spectrum.01874-22

Cited by 7 publications

(3 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The role of IgG in limiting disease within the lungs may be complemented by surfactant proteins A and D, which can opsonize mycobacteria ( 62 ). Our data differ from studies showing that NTM infections result in high levels of circulating IgG and IgA, which can be used to diagnose NTM infection ( 63 , 64 ). This difference could be due to the longer chronicity of disease in humans.…”

Section: Discussioncontrasting

confidence: 99%

Immunological and microbial shifts in the aging rhesus macaque lung during nontuberculous mycobacterial infection

Cinco,

Napier,

Rhoades

et al. 2024

mBio

View full text Add to dashboard Cite

Nontuberculous mycobacteria (NTM) are environmentally ubiquitous organisms that predominately cause NTM pulmonary disease (NTMPD) in individuals over the age of 65. The incidence of NTMPD has increased in the U.S., exceeding that of Mycobacterium tuberculosis . However, the mechanisms leading to higher susceptibility and severity of NTMPD with aging are poorly defined in part due to the lack of animal models that accurately recapitulate human disease. Here, we compared bacterial load, microbial communities, and host responses longitudinally between three young (two female and one male) and two aged (two female) rhesus macaques inoculated with Mycobacterium avium subsp. hominissuis (MAH) in the right caudal lobe. Unilateral infection resulted in a low bacterial load in both young and aged animals confined to the infected side. Although a robust inflammatory response was only observed in the inoculated lung, immune cell infiltration and antigen-specific T cells were detected in both lungs. Computed tomography, gross pathology, and histopathology revealed increased disease severity and persistence of bacterial DNA in aged animals. Additional analyses showed the translocation of gut and oral-pharyngeal bacterial DNA into the lower respiratory microbiome. Finally, single-cell RNA sequencing revealed a heightened inflammatory response to MAH infection by alveolar macrophages in aged animals. These data are consistent with the model that increased disease severity in the aged is mediated by a dysregulated macrophage response that may be sustained through persistent antigen presence. IMPORTANCE Nontuberculous mycobacteria (NTM) are emerging as pathogens of high consequence, as cases of NTM pulmonary disease (NTMPD) have exceeded those of Mycobacterium tuberculosis . NTMPD can be debilitating, particularly in patients over 65 years of age, as it causes chronic cough and fatigue requiring prolonged treatments with antibiotics. The underlying mechanisms of this increased disease severity with age are poorly understood, hampering the development of therapeutics and vaccines. Here, we use a rhesus macaque model to investigate the impact of age on host-NTM interactions. This work shows that aging is associated with increased disease severity and bacterial persistence in aged rhesus macaques, thus providing a preclinical model to develop and test novel therapeutics and interventions.

show abstract

Section: Discussioncontrasting

confidence: 99%

Immunological and microbial shifts in the aging rhesus macaque lung during nontuberculous mycobacterial infection

Cinco,

Napier,

Rhoades

et al. 2024

mBio

View full text Add to dashboard Cite

show abstract

“…Our studies focused on the role of non-immune plasma. We have previously demonstrated that anti-Mab IgG exist in NTM-infected people with CF (41), but the role of specific immunity on opsonization and killing will require further study. Finally, these studies focus on neutrophils; the role of complement for other immune cells working and in vivo effects require further study.…”

Section: Discussionmentioning

confidence: 97%

Divergent host innate immune response to the smooth-to-roughM. abscessusadaptation to chronic infection

Wheeler

Lenhart-Pendergrass

Rysavy

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Mycobacterium abscessus is a nontuberculous mycobacterium emerging as a significant pathogen for individuals with chronic lung disease, including cystic fibrosis and chronic obstructive pulmonary disease. Current therapeutics have poor efficacy. New strategies of bacterial control based on host defenses are appealing, but anti-mycobacterial immune mechanisms are poorly understood and are complicated by the appearance of smooth and rough morphotypes with distinct host responses. We explored the role of the complement system in the clearance of M. abscessus morphotypes by neutrophils, an abundant cell in these infections. M. abscessus opsonized with plasma from healthy individuals promoted greater killing by neutrophils compared to opsonization in heat-inactivated plasma. Rough clinical isolates were more resistant to complement but were still efficiently killed. Complement C3 associated strongly with the smooth morphotype while mannose-binding lectin 2 was associated with the rough morphotype. M. abscessus killing was dependent on C3, but not on C1q or Factor B; furthermore, competition of mannose-binding lectin 2 binding with mannan or N-acetyl-glucosamine during opsonization did not inhibit killing. These data suggest that M. abscessus does not canonically activate complement through the classical, alternative, or lectin pathways. Complement-mediated killing was dependent on IgG and IgM for smooth and on IgG for rough M. abscessus. Both morphotypes were recognized by Complement Receptor 3 (CD11b), but not CR1 (CD35), and in a carbohydrate- and calcium-dependent manner. These data suggest the smooth-to-rough adaptation changes complement recognition of M. abscessus and that complement is an important factor for M. abscessus infection.

show abstract

“…The role of IgG may be limited within the lungs since surfactant proteins (SP) A and D may opsonize mycobacteria [74]. Other studies showed that NTM infections result in high levels of circulating IgG and IgA which can be used to diagnose NTM infection [75, 76]. Moreover, it has been shown that antibodies have a functional role in the control of TB [77].…”

Section: Discussionmentioning

confidence: 99%

Impact of aging on the immunological and microbial landscape of the lung during non-tuberculous mycobacterial infection

Cinco¹,

Rhoades²,

Napier³

et al. 2023

Preprint

View full text Add to dashboard Cite

Nontuberculous mycobacteria (NTM) are environmentally ubiquitous and predominately cause pulmonary disease (NTMPD). The incidence of NTMPD has steadily increased and is now more prevalent than that of Mycobacterium tuberculosis (M. tb) in the US. Moreover, the prevalence of NTMPD increases with age; therefore, it is likely that the burden of NTMPD will continue to increase in the coming decades as the number of those over the age of 65 increased in the U.S population. However, the mechanisms leading to higher susceptibility and severity of NTMPD with aging are poorly defined. Here, we used a rhesus macaque model of intrabronchial infection with M. avium complex in young and aged animals to address this knowledge gap. Unilateral infection resulted in a robust inflammatory response predominantly in the inoculated lung, however, immune cell infiltration and antigen-specific T cell responses were detected in both lungs. Nasal, oral, and fecal swabs, and BAL samples were profiled using 16S amplicon sequencing. These data suggested that decompartmentalization of the lower respiratory microbiome was occurring, evidenced by detection of bacterial DNA typically found in the gut and oral-pharyngeal cavity in bronchoalveolar samples following infection. Radiographic studies, gross pathology, and histopathology examination revealed increased disease severity in aged compared to young animals with pulmonary consolidation, edema, and lesions. Finally, single cell RNA sequencing indicated that aged animals generated a dysregulated macrophage and CD8 T cell response to MAC infection.

show abstract

Specificity of Immunoglobulin Response to Nontuberculous Mycobacteria Infection in People with Cystic Fibrosis

Cited by 7 publications

References 37 publications

Immunological and microbial shifts in the aging rhesus macaque lung during nontuberculous mycobacterial infection

Immunological and microbial shifts in the aging rhesus macaque lung during nontuberculous mycobacterial infection

Divergent host innate immune response to the smooth-to-roughM. abscessusadaptation to chronic infection

Impact of aging on the immunological and microbial landscape of the lung during non-tuberculous mycobacterial infection

Contact Info

Product

Resources

About