REFERENCES

01. WHO - World Health Organization. Global tuberculosis report 2023. Available from: https://www.who.int/teams/global-tuberculosis- programme/tb-reports/global-tuberculosis-report-2023.

02. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017; 64(2): 111-5.

03. Chan ED, Heifets L, Iseman MD. Immunologic diagnosis of tuberculosis: a review. Tuber Lung Dis. 2000; 80(3): 131-40.

04. Baghaei P, Tabarsi P, Sabour H, Dehghani S, Marjani M, Shamaei M, et al. Detection of antibodies against 6, 16 and 38 kDa antigens of Mycobacterium tuberculosis as a rapid test for diagnosis of tuberculosis. Tanaffos. 2011; 10(4): 17-22.

05. Anochie PI, Onyeneke EC, Ogu AC, Onyeozirila AC, Aluru S, Onyejepu N, et al. Recent advances in the diagnosis of Mycobacterium tuberculosis. Germs. 2012; 2(3): 110-20.

06. Feng X, Yang X, Xiu B, Qie S, Dai Z, Chen K, et al. IgG, IgM and IgA antibodies against the novel polyprotein in active tuberculosis. BMC Infectious Diseases. 2014; 14: 336.

07. Sampson SL. Mycobacterial PE/PPE proteins at the host-pathogen interface. Clin Dev Immunol. 2011;2011: 497203.

08. Fishbein S, van Wyk N, Warren RM, Sampson SL. Phylogeny to function: PE/PPE protein evolution and impact on Mycobacterium tuberculosis pathogenicity. Mol Microbiol. 2015; 96(5): 901-16.

09. Brennan MJ. The enigmatic PE/PPE multigene family of Mycobacteria and tuberculosis vaccination. Infect Immun. 2017; 85(6): e00969-16.

10. Li Y, Miltner E, Wu M, Petrofsky M, Bermudez LE. A Mycobacterium avium PPE gene is associated with the ability of the bacterium to grow in macrophages and virulence in mice. Cell Microbiol. 2005; 7(4): 539-48.

11. Chakhaiyar P, Nagalakshmi Y, Aruna B, Murthy KJ, Katoch VM, Hasnain SE. Regions of high antigenicity within the hypothetical PPE major polymorphic tandem repeat open-reading frame,Rv2608, show a differential humoral response and a low T cell response in various categories of patients with tuberculosis. J Infect Dis. 2004; 190(7): 1237-44.

12. Khan N, Alam K, Nair S, Valluri VL, Murthy KJR, Mukhopadhyay S. Association of strong immune responses to PPE protein Rv1168c with active tuberculosis. Clin Vaccin Immunol. 2008; 15(6): 974-80.

13. Singh KK, Dong Y, Patibandla SA, McMurray DN, Arora VK, Laal S. Immunogenicity of the Mycobacterium tuberculosis PPE55 (Rv3347c) protein during incipient and clinical tuberculosis. Infect Immun. 2005; 73(8): 5004-14.

14. Chen J, Su X, Zhang Y, Wang S, Shao L, Wu J, et al. Novel recombinant RD2- and RD11-encoded Mycobacterium tuberculosis antigens are potential candidates for diagnosis of tuberculosis infections in BCG-vaccinated individuals. Microbes Infect. 2009; 11(10-11): 876-85.

15. Parkash O, Singh BP, Pai M. Regions of differences encoded antigens as targets for immunodiagnosis of tuberculosis in humans. Scand J Immunol. 2009; 70(4): 345-57.

16. Al-Attiyah R, Mustafa AS. Characterization of human cellular immune responses to novel Mycobacterium tuberculosis antigens encoded by genomic regions absent in Mycobacterium bovis BCG. Infect Immun. 2008; 76(9): 4190-8.

17. Silva VM, Sardella IG, Luiz RR, Cunha AJ, Cavalcanti AH, Mahavir S, et al. Immunoreactivity of five antigens of Mycobacterium tuberculosis in patients attending a public health care facility in an area with high endemicity for TB. Microbiol Immunol. 2008; 52(11): 544-50.

18. Sardella IG, Mulinari ACP, Fonseca LS, Saad MHF. Cloning, expression and characterization of fusion proteins based on peptides of Rv1980c disrupting Rv3019c sequence and evaluation of its potential immunoreactivity in pulmonary tuberculosis sera. Mycobact Dis. 2015; 5: 1-7.

19. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med. 2000; 161(4 Pt 1): 1376-95. doi: 10.1164/ajrccm.161.4.16141.

20. Zhang SL, Zhao JW, Sun ZQ, Yang EZ, Yan JH, Zhao Q, et al. Development and evaluation of a novel multiple-antigen ELISA for serodiagnosis of tuberculosis. Tuberculosis (Edinb). 2009; 89(4): 278-84.

21. Broger T, Roy RB, Filomena A, Greef CH, Rimmele S, Havumaki J, al. Diagnostic performance of tuberculosis-specific IgG antibody profiles in patients with presumptive tuberculosis from two continents. Clin Infect Dis. 2017; 64(7): 947-55.

22. Karboul A, Mazza A, van Pittius NCG, Ho JL, Brousseau R, Mardassi H. Frequent homologous recombination events in Mycobacterium tuberculosis PE/PPE multigene families: potential role in antigenic variability. J Bacteriol. 2008; 190(23): 7838-46.

23. Liaquat A, Iram S, Hussain S, Yusuf NW, Azeem H. Concomitant presence of culture-proven active pulmonary tuberculosis in patients with chronic obstructive pulmonary disease - A hospitalbased study. Pak J Med Sci. 2015; 31(6): 1344-48.

24. Akhter Y, Ehebauer MT, Mukhopadhyay S, Hasnain SE. The PE/ PPE multigene family codes for virulence factors and is a possible source of mycobacterial antigenic variation: perhaps more? Biochimie. 2012; 94(1): 110-6.

25. McEvoy CR, Cloete R, Müller B, Schürch AC, van Helden PD, Gagneux S, et al. Comparative analysis of Mycobacterium tuberculosis pe and ppe genes reveals high sequence variation and an apparent absence of selective constraints. PLoS One. 2012; 7(4): e30593.

26. Vordermeier HM, Hewinson RG, Wilkinson RJ, Wilkinson KA, Gideon HP, Young DB, et al. Conserved immune recognition hierarchy of mycobacterial PE/PPE proteins during infection in natural hosts. PLoS one. 2012; 7(8): e40890.

27. Zhang H, Wang J, Lei J, Zhang M, Yang Y, Chen Y, et al. PPE protein (Rv3425) from DNA segment RD11 of Mycobacterium tuberculosis: a potential B-cell antigen used for serological diagnosis to distinguish vaccinated controls from tuberculosis patients. Clin Microbiol Infect. 2007; 13(2): 139-45.

28. Gutlapalli R, Sykam A, Tenali SP, Chandran P, Suneetha S, Suneetha LM. Detection of tuberculosis in HIV co-infected individuals: use of multiple ELISA responses to 38kDa, lipoarabinomannan and ESAT- 6 of M. tuberculosis. J Clin Diagn Res. 2016; 10(2): KC01-4.

29. Chin ST, Ignatius J, Suraiya S, Tye GJ, Sarmiento ME, Acosta A, et al. Comparative study of IgA V H 3 gene usage in healthy TST - and TST + population exposed to tuberculosis: deep sequencing analysis. Immunology. 2015; 144: 302-11.

30. Xiao JN, Xiong Y, Chen Y, Xiao YJ, Ji P, Li Y, et al. Determination of lipoprotein Z-specific IgA in tuberculosis and latent tuberculosis infection. Front Cell Infect Microbiol. 2017; 7: 495.

31. Williams A, Reljic R, Naylor I, Clark SO, Falero-Diaz G, Singh M, et al. Passive protection with immunoglobulin A antibodies against tuberculous early infection of the lungs. Immunology. 2004; 111(3): 328-33.

32. Mertens JR, Flisher AJ, Ward CL, Bresick GF, Sterling SA, Weisner CM. Medical conditions of hazardous drinkers and drug users in primary care clinics in Cape Town, South Africa. J Drug Issues. 2009; 39(4): 75796776.

33. Louw JS, Mabaso M, Peltzer K. Change in health-related quality of life among pulmonary tuberculosis patients at primary health care settings in South Africa: a prospective cohort study. PLoS One. 2016; 11: e0151892.

34. Abebe F, Belay M, Legesse M, Franken KLMC, Ottenhoff THM. IgA and IgG against Mycobacterium tuberculosis Rv2031 discriminate between pulmonary tuberculosis patients, Mycobacterium tuberculosis-infected and non-infected individuals. PLoS One. 2018; 13(1): e0190989.

35. Kunnath-Velayudhan S, Salamon H, Wang HY, Davidow AL, Molina DM, Huynh VT, et al. Dynamic antibody responses to the Mycobacterium tuberculosis proteome. Proc Natl Acad Sci USA. 2010; 107(33): 14703-8.

Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 119 | 2024

Research Articles

PPE59 antibodies in tuberculous patients and potential use for diagnosis when assayed with other rapid biomarkers

Ana Carla de Paulo Mulinari¹, Isabela Gama Sardella¹, Vania Maria C da Silva², Alberto Matteelli³, Anna Cristina C Carvalho⁴, Maria Helena Féres Saad^1,+

¹Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Microbiologia Celular, Rio de Janeiro, RJ, Brasil
²Universidade Federal do Rio de Janeiro, Faculdade de Medicina, Rio de Janeiro, RJ, Brasil
³Università degli Studi di Brescia, Clinic of Infectious and Tropical Diseases, Spedali Civili di Brescia, Italy
⁴Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Educação e Bioprodutos, Rio de Janeiro, RJ, Brasil

DOI: 10.1590/0074-02760230183

5961 views 1168 downloads

Print PDF Supplementary data

ABSTRACT

BACKGROUND PPE 59, which is absent from bacillus Calmette Guérin (BCG) strains, seems to induce a humoral immune response in patients with tuberculosis (TB). Additional studies are needed to better evaluate this protein in immune response to tuberculosis.
OBJECTIVES To evaluate the response of antibodies to PPE59 in TB individuals, its combination with IgG response to other, previously tested mycobacterial antigens (Ag) and with sputum smear microbiology (SM) results.
METHODS We have cloned and expressed the rv3429 gene that encodes PPE59, then IgG, IgM, and IgA against PPE59 antigens measured by enzyme-linked immunosorbent assay (ELISA) in 212 sera samples obtained from the following subject cohorts: TB residents from Italy (79) and in Brazil (52); and an all-Brazilian cohort of 55 patients with other respiratory disorders; 10 patients infected with non-tuberculous mycobacteria, and 16 asymptomatic subjects. Drawing on results from a previous study⁽¹⁷⁾ of serum samples from Brazilian subjects tested for IgG by ELISA against mycobacterial antigens ESAT-6, 16kDa, MT10.3, MPT-64 and 38kDa, the results were analysed in combination with those of the PPE59 and SM tests.
FINDINGS Keeping the specificity rate at 97%, the overall PPE59 IgA sensitivity was 42.7%, while IgG and IgM showed lower performance (p < 0.0001). Combining PPE59 IgA/16kDa IgG results increased sensitivity to 71%, and even higher rates when the results were combined with SM results (86.5%, p = 0.001), at 88.9% specificity. Positive IgA was associated with pulmonary image alterations of high TB probability (p < 0.05).
MAIN CONCLUSIONS Tests with TB patients found a moderate frequency of positivity for PPE59 IgA. However, the higher level of sensitivity attained in combination with PPE59 IgA/16kDa IgG/SM results unheard of before, although imperfect, suggests that this may be a potential additional tool for rapid detection of TB in low-resource areas.

key words: Mycobacterium tuberculosis tuberculosis 16 kDa serology PPE59 (rv3429)

REFERENCES