1887

Abstract

Host genetic factors influence both susceptibility to infection and immune responses generated by vaccination. Genetically susceptible mice help to study mechanisms of immune protection which may differ from those operating in more resistant models.

In this work, we compared the efficacy of protection conferred by subcutaneous vaccination of hypersusceptible I/St mice with BCG and the first-generation, hygromycin resistant version of the vaccine candidate BCGΔBCG1419c, against tuberculosis (TB), measured as survival, weight loss and replication in lungs. We further characterized the relative presence of immune cells in lungs.

We found that in I/St mice, vaccination with BCG or BCGΔBCG1419c provided similar level of protection against TB-driven weight loss and replication in lungs, while prolonging median survival time compared with unvaccinated controls. Despite affording similar protection to parental BCG, BCGΔBCG1419c led to a reduced presence of macrophages in lungs during early TB and to an increased neutrophil recruitment to the lungs during chronic TB.

BCGΔBCG1419c protects I/St mice in a different manner than wild-type BCG against pulmonary TB by promoting different influx of macrophages and neutrophils at distinct times post-infection. These findings prompt us to suggest that preclinical evaluation of novel TB vaccine candidates should include evaluation of efficacy not only in commonly used resistant inbred mice, but also in susceptible hosts, to further determine their potential application to populations varying in their genetic. This would likely impact their intended use depending on host resistance or susceptibility to TB.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.001485
2022-01-17
2023-02-08
Loading full text...

Full text loading...

References

  1. Verhein KC, Vellers HL, Kleeberger SR. Inter-individual variation in health and disease associated with pulmonary infectious agents. Mamm Genome 2018; 29:38–47 [View Article] [PubMed]
    [Google Scholar]
  2. Lavebratt C, Apt AS, Nikonenko BV, Schalling M, Schurr E. Severity of tuberculosis in mice is linked to distal chromosome 3 and proximal chromosome 9. J Infect Dis 1999; 180:150–155 [View Article] [PubMed]
    [Google Scholar]
  3. Smith CM, Proulx MK, Olive AJ, Laddy D, Mishra BB et al. Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype. mBio 2016; 7:e01516-16 [View Article] [PubMed]
    [Google Scholar]
  4. Kurtz SL, Rossi AP, Beamer GL, Gatti DM, Kramnik I et al. The diversity outbred mouse population is an improved animal model of vaccination against tuberculosis that reflects heterogeneity of protection. mSphere 2020; 5:e00097-20 [View Article] [PubMed]
    [Google Scholar]
  5. Flores-Valdez MA, Pedroza-Roldán C, de Jesus Aceves-Sánchez M, Peterson EJR, Baliga NS et al. The BCGΔBCG1419c vaccine candidate reduces lung pathology, IL-6, TNF-α, and IL-10 during chronic TB infection. Front Microbiol 2018; 9:1281 [View Article] [PubMed]
    [Google Scholar]
  6. Pedroza-Roldán C, Guapillo C, Barrios-Payán J, Mata-Espinosa D, de Jesus Aceves-Sánchez M et al. The BCGΔBCG1419c strain, which produces more pellicle in vitro, improves control of chronic tuberculosis in vivo. Vaccine 2016; 34:4763–4770 [View Article] [PubMed]
    [Google Scholar]
  7. Flores-Valdez MA, de Jesus Aceves-Sánchez M, Pedroza-Roldán C, Vega-Domínguez PJ, Prado-Montes de Oca E et al. The cyclic Di-GMP phosphodiesterase gene Rv1357c/BCG1419c affects BCG pellicle production and in vivo maintenance. IUBMB Life 2015; 67:129–138 [View Article] [PubMed]
    [Google Scholar]
  8. Radaeva TV, Kondratieva EV, Sosunov VV, Majorov KB, Apt A. A human-like TB in genetically susceptible mice followed by the true dormancy in a Cornell-like model. Tuberculosis (Edinb) 2008; 88:576–585 [View Article] [PubMed]
    [Google Scholar]
  9. Nikonenko BV, Averbakh MM, Lavebratt C, Schurr E, Apt AS. Comparative analysis of mycobacterial infections in susceptible I/St and resistant A/Sn inbred mice. Tuber Lung Dis 2000; 80:15–25 [View Article] [PubMed]
    [Google Scholar]
  10. Nikonenko BV, Logunova NN, Sterzhanova NV, Kayukova SI, Apt AS. Efficacy of BCG vaccination depends on host genetics. Bull Exp Biol Med 2021; 171:445–448 [View Article] [PubMed]
    [Google Scholar]
  11. Majorov KB, Lyadova IV, Kondratieva TK, Eruslanov EB, Rubakova EI et al. Different innate ability of I/St and A/Sn mice to combat virulent Mycobacterium tuberculosis: phenotypes expressed in lung and extrapulmonary macrophages. Infect Immun 2003; 71:697–707 [View Article] [PubMed]
    [Google Scholar]
  12. Eruslanov EB, Majorov KB, Orlova MO, Mischenko VV, Kondratieva TK et al. Lung cell responses to M. tuberculosis in genetically susceptible and resistant mice following intratracheal challenge. Clin Exp Immunol 2004; 135:19–28 [View Article] [PubMed]
    [Google Scholar]
  13. Henao-Tamayo M, Obregón-Henao A, Creissen E, Shanley C, Orme I et al. Differential Mycobacterium bovis BCG vaccine-derived efficacy in C3Heb/FeJ and C3H/HeOuJ mice exposed to a clinical strain of Mycobacterium tuberculosis . Clin Vaccine Immunol 2015; 22:91–98 [View Article] [PubMed]
    [Google Scholar]
  14. Yan B-S, Pichugin AV, Jobe O, Helming L, Eruslanov EB et al. Progression of pulmonary tuberculosis and efficiency of bacillus Calmette-Guérin vaccination are genetically controlled via a common sst1-mediated mechanism of innate immunity. J Immunol 2007; 179:6919–6932 [View Article] [PubMed]
    [Google Scholar]
  15. Lee J, Boyce S, Powers J, Baer C, Sassetti CM et al. CD11cHi monocyte-derived macrophages are a major cellular compartment infected by Mycobacterium tuberculosis. PLoS Pathog 2020; 16:e1008621 [View Article]
    [Google Scholar]
  16. Lyadova IV. Neutrophils in tuberculosis: heterogeneity shapes the way?. Mediators Inflamm 2017; 2017:8619307 [View Article] [PubMed]
    [Google Scholar]
  17. Yeremeev V, Linge I, Kondratieva T, Apt A. Neutrophils exacerbate tuberculosis infection in genetically susceptible mice. Tuberculosis (Edinb) 2015; 95:447–451 [View Article] [PubMed]
    [Google Scholar]
  18. Eruslanov EB, Lyadova IV, Kondratieva TK, Majorov KB, Scheglov IV et al. Neutrophil responses to Mycobacterium tuberculosis infection in genetically susceptible and resistant mice. Infect Immun 2005; 73:1744–1753 [View Article] [PubMed]
    [Google Scholar]
  19. Junqueira-Kipnis AP, Trentini MM, Marques Neto LM, Kipnis A. Live vaccines have different NK cells and neutrophils requirements for the development of a protective immune response against tuberculosis. Front Immunol 2020; 11:741 [View Article] [PubMed]
    [Google Scholar]
  20. de Jesus Aceves-Sánchez M, Flores-Valdez MA, Pedroza-Roldán C, Creissen E, Izzo L et al. Vaccination with BCGΔBCG1419c protects against pulmonary and extrapulmonary TB and is safer than BCG. Sci Rep 2021; 11:12417 [View Article] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.001485
Loading
/content/journal/jmm/10.1099/jmm.0.001485
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error