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1. Zinc-limited Mycobacterium tuberculosis stimulate distinct responses in macrophages compared with standard zinc-replete bacteria

   https://doi.org/10.1128/iai.00578-24  

   Marcantonio, Endrei; Burger, Allexa D; Chang, Kelly H; Hoffmann, Fukun W; Fu, Yuanyuan; Khadka, Vedbar S; Smagghe, Benoit J; Deng, Youping; Hoffmann, Peter R; Prisic, Sladjana (March 2025, Infection and Immunity)

   Shin, Sunny (Ed.)

   ABSTRACT Tuberculosis (TB) is notoriously difficult to treat, likely due to the complex host-pathogen interactions driven by pathogen heterogeneity. An understudied area of TB pathogenesis is host responses toMycobacterium tuberculosisbacteria (Mtb) that are limited in zinc ions. This distinct population resides in necrotic granulomas and sputum and could be the key player in tuberculosis pathogenicity. In this study, we tested the hypothesis that macrophages differentiate between Mtb grown under zinc limitation or in the standard zinc-replete medium. Using several macrophage infection models, such as murine RAW 264.7 and murine bone marrow-derived macrophages (BMDMs), as well as human THP-1-derived macrophages, we show that macrophages infected with zinc-limited Mtb have increased bacterial burden compared with macrophages infected with zinc-replete Mtb. We further demonstrate that macrophage infection with zinc-limited Mtb trigger higher production of reactive oxygen species (ROS) and cause more macrophage death. Furthermore, the increased ROS production is linked to the increased phagocytosis of zinc-limited Mtb, whereas cell death is not. Finally, transcriptional analysis of RAW 264.7 macrophages demonstrates that macrophages have more robust pro-inflammatory responses when infected with zinc-limited Mtb than zinc-replete Mtb. Together, our findings suggest that Mtb’s access to zinc affects their interaction with macrophages and that zinc-limited Mtb may be influencing TB progression. Therefore, zinc availability in bacterial growth medium should be considered in TB drug and vaccine developments. 

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2. Multi-Omics Profiling Specifies Involvement of Alternative Ribosomal Proteins in Response to Zinc Limitation in Mycobacterium smegmatis

   https://doi.org/10.3389/fmicb.2022.811774  

   Dow, Allexa; Burger, Andrew; Marcantonio, Endrei; Prisic, Sladjana (February 2022, Frontiers in Microbiology)

   Zinc ion (Zn 2+ ) is an essential micronutrient and a potent antioxidant. However, Zn 2+ is often limited in the environment. Upon Zn 2+ limitation, Mycolicibacterium (basonym: Mycobacterium ) smegmatis (Msm) undergoes a morphogenesis, which relies on alternative ribosomal proteins (AltRPs); i.e., Zn 2+ -independent paralogues of Zn 2+ -dependent ribosomal proteins. However, the underlying physiological changes triggered by Zn 2+ limitation and how AltRPs contribute to these changes were not known. In this study, we expand the knowledge of mechanisms utilized by Msm to endure Zn 2+ limitation, by comparing the transcriptomes and proteomes of Zn 2+ -limited and Zn 2+ -replete Msm . We further compare, corroborate and contrast our results to those reported for the pathogenic mycobacterium, M. tuberculosis , which highlighted conservation of the upregulated oxidative stress response when Zn 2+ is limited in both mycobacteria. By comparing the multi-omics analysis of a knockout mutant lacking AltRPs (Δ altRP ) to the Msm wild type strain, we specify the involvement of AltRPs in the response to Zn 2+ limitation. Our results show that AltRP expression in Msm does not affect the conserved oxidative stress response during Zn 2+ limitation observed in mycobacteria, but AltRPs do significantly impact expression patterns of numerous genes that may be involved in morphogenesis or other adaptive responses. We conclude that AltRPs are not only important as functional replacements for their Zn 2+ -dependent paralogues; they are also involved in the transcriptomic response to the Zn 2+ -limited environment. 

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3. Metal-induced oxidative stress and human plasma protein oxidation after SARS-CoV-2 infection

   https://doi.org/10.1038/s41598-023-29119-5  

   Aryal, Baikuntha; Tillotson, Joseph; Ok, Kiwon; Stoltzfus, Andrew T.; Michel, Sarah L. J.; Rao, V. Ashutosh (February 2023, Scientific Reports)

   Abstract Pathogenesis of COVID-19 by SARS-CoV-2 resulted in a global pandemic and public health emergency in 2020. Viral infection can induce oxidative stress through reactive oxygen species (ROS). Inflammation and environmental stress are major sources of oxidative stress after infection. Micronutrients such as iron, copper, zinc, and manganese play various roles in human tissues and their imbalance in blood can impact immune responses against pathogens including SARS CoV-2. We hypothesized that alteration of free metal ions during infection and metal-catalyzed oxidation plays a critical role towards pathogenesis after infection. We analyzed convalescent and hospitalized COVID-19 patient plasma using orthogonal analytical techniques to determine redox active metal concentrations, overall protein oxidation, oxidative modifications, and protein levels via proteomics to understand the consequences of metal-induced oxidative stress in COVID-19 plasma proteins. Metal analysis using ICP-MS showed significantly greater concentrations of copper in COVID-19 plasma compared to healthy controls. We demonstrate significantly greater total protein carbonylation, other oxidative modifications, and deamidation of plasma proteins in COVID-19 plasma compared to healthy controls. Proteomics analysis showed that levels of redox active proteins including hemoglobulin were elevated in COVID-19 plasma. Molecular modeling concurred with potential interactions between iron binding proteins and SARS CoV-2 surface proteins. Overall, increased levels of redox active metals and protein oxidation indicate that oxidative stress-induced protein oxidation in COVID-19 may be a consequence of the interactions of SARS-CoV-2 proteins with host cell metal binding proteins resulting in altered cellular homeostasis. 

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4. Colony-stimulating factor-1- and interleukin-34-derived macrophages differ in their susceptibility to Mycobacterium marinum

   https://doi.org/10.1002/JLB.1A0919-147R  

   Popovic, Milan; Yaparla, Amulya; Paquin-Proulx, Dominic; Koubourli, Daphne V.; Webb, Rose; Firmani, Marcia; Grayfer, Leon (September 2019, Journal of Leukocyte Biology)

   Abstract Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains the leading global cause of death from an infectious agent. Mycobacteria thrive within their host Mϕs and presently, there is no animal model that permits combined in vitro and in vivo study of mycobacteria-host Mϕ interactions. Mycobacterium marinum (Mm), which causes TB in aquatic vertebrates, has become a promising model for TB research, owing to its close genetic relatedness to Mtb and the availability of alternative, natural host aquatic animal models. Here, we adopted the Xenopus laevis frog-Mm surrogate infection model to study host Mϕ susceptibility and resistance to mycobacteria. Mϕ differentiation is regulated though the CSF-1 receptor (CSF-1R), which is activated by CSF-1 and the unrelated IL-34 cytokines. Using combined in vitro and in vivo approaches, we demonstrated that CSF-1-Mϕs exacerbate Mm infections, are more susceptible to mycobacterial entry and are less effective at killing this pathogen. By contrast, IL-34-Mϕs confer anti-Mm resistance in vivo, are less susceptible to Mm entry and more effectively eliminate internalized mycobacteria. Moreover, we showed that the human CSF-1- and IL-34-Mϕs are likewise, respectively, susceptible and resistant to mycobacteria, and that both frog and human CSF-1-Mϕs are more prone to the spread of mycobacteria and to being infected by Mm-laden Mϕs than the respective IL-34-Mϕ subsets. This work marks the first report describing the roles of these Mϕ subsets in mycobacterial disease and may well lead to the development of more targeted anti-Mtb approaches. 

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5. Spatial variation in gene expression of Tasmanian devil facial tumors despite minimal host transcriptomic response to infection

   https://doi.org/10.1186/s12864-021-07994-4  

   Kozakiewicz, Christopher P.; Fraik, Alexandra K.; Patton, Austin H.; Ruiz-Aravena, Manuel; Hamilton, David G.; Hamede, Rodrigo; McCallum, Hamish; Hohenlohe, Paul A.; Margres, Mark J.; Jones, Menna E.; et al (December 2021, BMC Genomics)

   Abstract Background Transmissible cancers lie at the intersection of oncology and infectious disease, two traditionally divergent fields for which gene expression studies are particularly useful for identifying the molecular basis of phenotypic variation. In oncology, transcriptomics studies, which characterize the expression of thousands of genes, have identified processes leading to heterogeneity in cancer phenotypes and individual prognoses. More generally, transcriptomics studies of infectious diseases characterize interactions between host, pathogen, and environment to better predict population-level outcomes. Tasmanian devils have been impacted dramatically by a transmissible cancer (devil facial tumor disease; DFTD) that has led to widespread population declines. Despite initial predictions of extinction, populations have persisted at low levels, due in part to heterogeneity in host responses, particularly between sexes. However, the processes underlying this variation remain unknown. Results We sequenced transcriptomes from healthy and DFTD-infected devils, as well as DFTD tumors, to characterize host responses to DFTD infection, identify differing host-tumor molecular interactions between sexes, and investigate the extent to which tumor gene expression varies among host populations. We found minimal variation in gene expression of devil lip tissues, either with respect to DFTD infection status or sex. However, 4088 genes were differentially expressed in tumors among our sampling localities. Pathways that were up- or downregulated in DFTD tumors relative to normal tissues exhibited the same patterns of expression with greater intensity in tumors from localities that experienced DFTD for longer. No mRNA sequence variants were associated with expression variation. Conclusions Expression variation among localities may reflect morphological differences in tumors that alter ratios of normal-to-tumor cells within biopsies. Phenotypic variation in tumors may arise from environmental variation or differences in host immune response that were undetectable in lip biopsies, potentially reflecting variation in host-tumor coevolutionary relationships among sites that differ in the time since DFTD arrival. 

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