Citation: Neimark H, Gesner M (2010) Is Mycoplasma pneumoniae Adherence to Erythrocytes a Factor in Extrapulmonary Dissemination? PLoS Pathog 6(12): e1001219. https://doi.org/10.1371/journal.ppat.1001219
Editor: Glenn F. Rall, The Fox Chase Cancer Center, United States of America
Published: December 23, 2010
Copyright: © 2010 Neimark, Gesner. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Mycoplasma pneumoniae is one of the most common causes of respiratory infections in children and adults worldwide , . This bacterial pathogen is estimated to be responsible for at least one case of pneumonia per 1,000 persons and >100,000 adult hospitalizations per year in the United States alone –. The infection is mostly mild, but all age groups can experience more severe disease, and fatal cases occasionally occur.
Extrapulmonary manifestations are a notable aspect of M. pneumoniae infections and are seen in up to 25% of infected persons , , . It has been pointed out that the high prevalence of M. pneumoniae infection in most populations predisposes to reporting concurrent but perhaps unrelated events as if they were part of the disease , and this may be so particularly for single case reports confirmed only by serologic response , . Among reported extrapulmonary manifestations, joint, skin, hematologic, cardiovascular, nervous, and immune system disorders are solidly documented by culture, polymerase chain reaction (PCR), immunohistochemical analysis, and/or serologic analysis , , –.
Characteristics of M. pneumoniae suggest the possibility that this mycoplasma could adhere to erythrocytes during extrapulmonary dissemination and such adherence could contribute to pathogenesis. First, M. pneumoniae has been cultured from extrapulmonary infection sites such as synovial fluid and pericardial fluid , , , so reaching such sites demonstrates that M. pneumoniae must be able to enter the blood stream. Second, it has long been known that M. pneumoniae adheres to human erythrocytes in vitro , , and electron microscopy shows M. pneumoniae does not merely adhere to erythrocytes but deforms them by producing depressions in the erythrocyte surface in which the mycoplasmas adhere closely . Third, M. pneumoniae belongs to the same phylogenetic group that contains the hemotropic mycoplasmas; these uncultivated mycoplasmas parasitize erythrocytes of mammalian hosts and produce acute and chronic blood infections with hemolytic anemia and other illness . Hemotropic mycoplasmas deform host erythrocytes and produce depressions in which they also adhere closely, and it is striking that the erythrocyte adherence of M. pneumoniae seen in vitro  appears to be identical to that observed in hemotropic mycoplasma erythrocyte infections . Further, M. pneumoniae famously causes half or more of patients to produce erythrocyte cold agglutinins, and this character also is shared with hemotropic mycoplasmas . We note that there is a report that a hemotropic mycoplasma can invade erythrocytes .
Some notion of the frequency of blood entry by M. pneumoniae may be provided by PCR studies that have demonstrated M. pneumoniae DNA in serum –. M. pneumoniae DNA has been detected in sera from pediatric patients both with pneumonia (1/25) and, significantly, without pneumonia (10/17), and in some cases M. pneumoniae DNA was detected for periods of more than 20 days, suggesting a bacteremia . A real-time PCR study that utilized archival sera mainly from adults found M. pneumoniae DNA in 15 of 29 seropositive patient sera . If these findings and other PCR reports detecting M. pneumoniae DNA in interior tissues often reflects the presence of organisms, as is thought by many investigators, then blood entry by M. pneumoniae might not be rare.
It may be necessary, nonetheless, to examine blood from a number of patients because of variables that could affect the presence of M. pneumoniae in a given sample. These include the frequency with which infection leads to blood entry, the infection stage(s) during which M. pneumoniae may enter the blood, the dwell period in blood, and the patient's immune status. The genotype of the infecting strain – also could be a factor in blood entry.
Rapid identification of M. pneumoniae infections by PCR – permits selection of appropriate cases for investigating the possibility that M. pneumoniae adheres to patient erythrocytes. The following information about hemotropic mycoplasma infections may be helpful in examining this possibility. Hemotropic mycoplasma infections have been detected mainly by visual search for erythrocyte-attached mycoplasmas in Wright-Giemsa blood smears, a relatively insensitive method, by animal inoculation, and by PCR (the current standard), but also of course by other molecular biological and instrument-based methods, including fluorescent-activated cell sorting. The percentage of infected erythrocytes in stained smears can vary from extremely high values (one or more mycoplasmas are seen attached to nearly every erythrocyte in most microscope fields) to very low values (searches of replicate smears from a PCR positive blood are negative), depending on, importantly, not only the stage of the infection but also the Mycoplasma species. Immuofluorescent or DNA staining substantially improves visual searching, and fluorescent staining allows more sensitive examination of archival Wright-Giemsa stained slides . Specific staining also permits identification of mycoplasmas free in the plasma that by light microscopy might be mistaken for nonbacterial particles.
Obtaining proof that M. pneumoniae has the ability to adhere to patient erythrocytes would enlarge our understanding of M. pneumoniae pathogenicity and provide an intriguing new perspective on how this mycoplasma disseminates in the bloodstream to produce extrapulmonary disease.
- 1. Waites KB, Talkington DF (2004) Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev 17: 697–728.
- 2. Baum SJ (2005) Mycoplasma pneumoniae and atypical pneumonia. In: Bennett's principles and practice of infectious diseases. , Mandell D, editors. Philadelphia: Elsevier. pp. 2271–2280.
- 3. Lauderdale TL, Chang FY, Ben RJ, Yin HC, Ni YH, et al. (2005) Etiology of community acquired pneumonia among adult patients requiring hospitalization in Taiwan. Respir Med 99: 1079–1086.
- 4. Stamm B, Moschopulos M, Hungerbuehler H, Guarner J, Genrich GI, et al. (2008) Neuroinvasion by Mycoplasma pneumoniae in acute disseminated encephalomyelitis. Emerg Infect Dis 14: 641–643.
- 5. Narita M (2010) Pathogenesis of extrapulmonary manifestations of Mycoplasma pneumoniae infection with special reference to pneumonia. J Infect Chemother 16: 162–169.
- 6. Atkinson TP, Balish MF, Waites KB (2008) Epidemiology, clinical manifestations, pathogenesis and laboratory detection of Mycoplasma pneumoniae infections. FEMS Microbiol Rev 32: 956–973.
- 7. Waites KB, Balish MF, Atkinson TP (2008) New insights into the pathogenesis and detection of Mycoplasma pneumoniae infections. Future Microbiol 3: 635–648.
- 8. Manchee RJ, Taylor-Robinson D (1968) Haemadsorption and haemagglutination by mycoplasmas. J Gen Microbiol 50: 465–478.
- 9. Baseman JB, Banai M, Kahane I (1982) Sialic acid residues mediate Mycoplasma pneumoniae attachment to human and sheep erythrocytes. Infect Immun 38: 389–391.
- 10. Deas JE, Janney FA, Lee LT, Howe C (1979) Immune electron microscopy of cross-reactions between Mycoplasma pneumoniae and human erythrocytes. Infect Immun 24: 211–217.
- 11. Neimark H, Johansson KE, Rikihisa Y, Tully JG (2001) Proposal to transfer some members of the genera Haemobartonella and Eperythrozoon to the genus Mycoplasma with descriptions of ‘Candidatus Mycoplasma haemofelis’, ‘Candidatus Mycoplasma haemomuris’, ‘Candidatus Mycoplasma haemosuis’ and ‘Candidatus Mycoplasma wenyonii’. Int J Syst Evol Microbiol 51: 891–899.
- 12. Neimark H, Barnaud A, Gounon P, Michel JC, Contamin H (2002) The putative haemobartonella that influences Plasmodium falciparum parasitaemia in squirrel monkeys is a haemotropic mycoplasma. Microbes Infect 4: 693–698.
- 13. Groebel K, Hoelzle K, Wittenbrink MM, Ziegler U, Hoelzle LE (2009) Mycoplasma suis invades porcine erythrocytes. Infect Immun 77: 576–584.
- 14. Narita M, Matsuzono Y, Itakura O, Togashi T, Kikuta H (1996) Survey of mycoplasmal bacteremia detected in children by polymerase chain reaction. Clin Infect Dis 23: 522–525.
- 15. Narita M, Yamada S, Nakayama T, Sawada H, Nakajima M, et al. (2001) Two cases of lymphadenopathy with liver dysfunction due to Mycoplasma pneumoniae infection with mycoplasmal bacteraemia without pneumonia. J Infect 42: 154–156.
- 16. Daxboeck F, Khanakah G, Bauer C, Stadler M, Hofmann H, et al. (2005) Detection of Mycoplasma pneumoniae in serum specimens from patients with mycoplasma pneumonia by PCR. Int J Med Microbiol 295: 279-285. Erratum: Int J Med Microbiol 2006; 55:
- 17. Dorigo-Zetsma JW, Dankert J, Zaat SA (2000) Genotyping of Mycoplasma pneumoniae clinical isolates reveals eight P1 subtypes within two genomic groups. J Clin Microbiol 38: 965–970.
- 18. Kenri T, Okazaki N, Yamazaki T, Narita M, Izumikawa K, et al. (2008) Genotyping analysis of Mycoplasma pneumoniae clinical strains in Japan between 1995 and 2005: type shift phenomenon of M. pneumoniae clinical strains. J Med Microbiol 57: 469–475.
- 19. Dumke R, Von Baum H, Lück PC, Jacobs E (2010) Subtypes and variants of Mycoplasma pneumoniae: local and temporal changes in Germany 2003-2006 and absence of a correlation between the genotype in the respiratory tract and the occurrence of genotype-specific antibodies in the sera of infected patients. Epidemiol Infect 25: 1–9.
- 20. Hansen EJ, Wilson RM, Baseman JB (1979) Isolation of mutants of Mycoplasma pneumoniae defective in hemadsorption. Infect Immun 23: 903–906.
- 21. Winchell JM, Thurman KA, Mitchell SL, Thacker WL, Fields BS (2008) Evaluation of three real-time PCR assays for detection of Mycoplasma pneumoniae in an outbreak investigation. J Clin Microbiol 46: 3116–3118.
- 22. Touati A, Benard A, Ben Hassen A, Bébéar CM, Pereyre S (2009) Evaluation of five commercial real-time PCR assays for the detection of Mycoplasma pneumoniae in respiratory tract specimens. J Clin Microbiol 47: 2268–2271.
- 23. Dumke R, Jacobs E (2009) Comparison of commercial and in-house real-time PCR assays used for detection of Mycoplasma pneumoniae. J Clin Microbiol 47: 441–444.
- 24. Kobayashi Y, Kimura S, Tanaka K, Wada K, Ozawa M, et al. (1991) Shift in the megakaryocyte ploidy in MDS patients: microcytofluorometry with DAPI staining after destaining of Wright-Giemsa stain. Br J Haematol 79: 556–561.