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. 2017 May 4;8:717. doi: 10.3389/fmicb.2017.00717

Table 1.

Characteristics and utilization of TB animal models.

Animal strains Strain selection Infection method Model type Pros in medical research Cons in medical research Application
C57BL/6
BALB/c
C3HeB/FeJ
mice		 H37Rv Multi-drug resistant
Mycobacterium tuberculosis (MDR) (105–107CFU)		 Tail vein, aerosol Active TB

  1. Small size, easy to operate, low cost

  2. Have clear genetic background, abundant immune reagent, immune mechanism of TB can be studied in mice (Nicolle et al., 2004; Calderon et al., 2013; Commandeur et al., 2014)

  3. The role of certain genes or proteins in tuberculosis mechanisms could be investigated in genetically engineered mice (Calderon et al., 2013; Olleros et al., 2015)

  4. Humanized mouse TB model could be a candidate model of HIV and TB co-infection (Nusbaum et al., 2016)

  1. No obvious clinical manifestation of tuberculosis infection (Lanoix et al., 2015; Lanoix, 2016)

  2. The TB granuloma structure is different to that of humans, without Langhans giant cells and class epithelioid cells in peripheral granulomas, do not form necrotic lesions in granuloma except in C3HeB/FeJ mice strain (Lanoix et al., 2015; Lanoix, 2016)

  3. No disseminated disease throughout the whole body (Shi et al., 2011)

  4. Inter-individual variation in infection outcome. Both pathological lesions and bacterial loads in organs were non-uniform (Scanga et al., 1999; Botha and Ryffel, 2002; Jacobs et al., 2015)

  1. Research on mechanisms of TB immunological response

  2. Role of a specific gene in TB

  3. Rapid evaluation of anti-tuberculosis drugs and vaccines (Gouveia et al., 2013; Izzo et al., 2015)
C57BL/6
C3HeB/FeJ
mice		 H37Rv 102–103 CFU Tail vein, aerosol Latent TB infection (LTBI)

  1. Spontaneous LTBI model could be obtained (Zhan et al., 2015)

  2. Modified LTBI model could also be obtained after drug or vaccine intervention (Lenaerts et al., 2004; Nuermberger et al., 2004)

  3. Mild granulomas lesions appeared in lung, spleen, and liver. Bacteria burdens kept low level throughout the latency phase, then relapsed with aggravated lesion and higher bacteria load levels (Zhang et al., 2009)

  1. The latency length and relapse level of TB show great variation within group, and the latent-relapse period very long (Myllymaki et al., 2015)

  2. Tissue bacterial loads were at high level at latency phase

  3. Lack of predictors for recurrence (Shi et al., 2011)

  1. Research on mechanisms of latency and relapse

  2. Research on prevention and control of the incubation period, including development of drugs and vaccines
Hartz guinea pig H37Rv 103–105
CFU		 Aerosol, subcutaneous Active TB, several kinds of vaccine evaluation

  1. Very susceptible to TB

  2. Miliary nodules observed in lung, liver, and spleen; tuberculous granuloma very similar to that in humans, with caseous necrosis (Kashino et al., 2008; Clark et al., 2015)

  3. Anti-TB drugs and vaccination have a good response (Clark et al., 2015)

  1. Lack of specific immune reagents, so more difficult to research underlying mechanisms (Clark et al., 2015)

  2. Lack of general clinical manifestations of TB (Kashino et al., 2008; Clark et al., 2015)

  3. Cannot spontaneously develop latent infection (Kashino et al., 2008)

  1. Drug evaluation

  2. Evaluation the safty and efficacy of vaccines or immunity strategies, such as primary immunity, prime-boost, and therapeutic vaccines

  3. pathological response of host, Mtb coevolution in vivo
The New Zealand rabbit H37Rv 108
CFU		 Spinal punching, aerosol Pulmonary, bone, meningeal, and cutaneous TB (Manabe et al., 2008; Dannenberg, 2009; Sun et al., 2012; Peng et al., 2015; Rahyussalim et al., 2016)

  1. TB granulomas with necrosis and liquefaction, and easy to form cavitation

  2. Rabbit spinal tuberculosis was the best model to research treatment of bone tuberculosis

  3. Model for rarer forms of TB (cutaneous and meningeal

  1. Clinical symptoms of TB not obvious

  2. Lack of relevant immune reagent

  3. Less susceptible to TB than guinea pigs, although slightly higher than mice

  1. Preferred model for research on diagnosis and treatment of cavitary, spinal, and joint TB

  2. Good model for TB transmission research

  3. Could also be used for diagnosis and research of meningeal and cutaneous TB
Cynomolgus macaque/Rhesus monkey H37Rv, Erdman, MDR 100–500
CFU		 Via bronchoscope LTBI and active TB (Scanga and Flynn, 2014; Izzo et al., 2015; Pena and Ho, 2015; Phuah et al., 2016)

  1. Can mimic a variety of clinical manifestations, such as low fever, emaciation, cough, depressed, and dyspnea

  2. Can mimic LTBI and various forms of active TB progression

  3. Can develop pulmonary TB as well as extra-pulmonary in the liver, spleen, kidney, mediastinum, and occasionally the cerebellum and bone.

  4. Granuloma structure similar to humans, with classic Langerhans giant cells

  1. Transgenic monkeys difficult to obtain, and limited availability of immune reagent, restricting the study of specific genes in TB

  2. High cost and space requirements limit the number of animals that can be used

  3. High variation within groups, making it difficult to evaluate the effectiveness of drugs and vaccines

  1. Evaluation of individualized anti-tuberculosis drugs and vaccines, treatment strategy

  2. Study of the personalized mechanisms of disease, including pathological and immological response of host, Mtb coevolution in vivo (precision medecine)
Chinese tree shrew H37Rv 103–106
CFU		 Caudal vein, Inguinal vein Active TB, TB-related pleural effusion (Zhan et al., 2014)

  1. Have weight loss, low fever, reduced mobility

  2. Visible TB nodules in peritoneum, lung, kidneys, region along spine, and intercostal space

  3. Cutaneous lesions and pleural effusion common; cerebellar TB can be established

  4. Proteomics, and transcriptomics can be used to study the mechanism of TB

  1. Clinical manifestation not obvious

  2. Granuloma structure different from human in lacking Langhans cells and caseous necrosis

  3. The same infection dose leads to different degrees of pathological changes

  4. The whole genome has been sequenced but not annotated

  5. Lack of immunological reagents.

  1. Research on TB treatment against pulmonary, pleural effusion, cutaneous tuberculosis models

  2. Research on pathogenic mechanisms of Mtb
Wistar rat HN878/W4 500
CFU		 Tracheotomy LTBI and active TB (Singhal et al., 2011a,b)

  1. Lower cost, compared to larger animals

  2. Continuous latent infections facilitate study of biological characteristics of TB bacterium from early to late dormant phase

  3. Formation of pulmonary granuloma containing lymphocytes, macrophages, and PMN

  4. TB model could be obtained in genetic engineering rat

  1. Relatively high pulmonary bacterial load in latent infection

  2. Granuloma structure dissimilar to that of human TB

  3. Rat are more resistant to Mtb infection than mice

  1. Research on anti-TB drug absorption, distribution, metabolism, toxicology, and efficacy of drug

  2. TB-related gene and protein would be investigated in genetic engineering rat.
Castrated male
Friesian-cross calf		 Mycobacterium bovis 104
CFU, Mycobacterium avium chester		 Aerosol Bovine TB

  1. Pathological lesions observed around the lower respiratory tract, the upper, middle, and lower lung lobes, and mediastinal lymph nodes. Mtb culture also positive (Rodgers et al., 2007; Plattner et al., 2009)

  2. Good model for research on TB susceptibility genes (Driscoll et al., 2011)

  3. Fetal bovine TB model good for immune response research; difference in γδT cells in early granuloma formation led to the different anti-tuberculosis response in host (Plattner et al., 2009)

  1. Have both intact and interrupt structural granulomas, both of which are different to that of human

  2. The ruptured granulomas is different to that of humans. In early phase, macrophages, lymphocytes, and a small amount of plasma cells make up the loose granuloma; in late phase, the scattered granulomas were encircled with epithelial cells but not fibroepithelial cells, and with necrosisor mineral deposits in the center,the majority of cells were WC1 (Baldwin and Telfer, 2015)

  3. The intact structural granulomas consisted of epithelial cell around granulomas and necrosis or cavitation in the center. Intact granulomas were comprised of γδT cells, Langerhans giant cells scattered in local lesions.(Plattner et al., 2009; Baldwin and Telfer, 2015)

  1. Investigate the protective effects of vaccines (Vordermeier et al., 2001)

  2. Research immune response mechanism of TB (Plattner et al., 2009; Driscoll et al., 2011; Waters et al., 2011; Baldwin and Telfer, 2015)

  3. Good model for research on TB susceptibility genes
Zebrafish larvae and adult Mycobacterium marinum Local injection, Caudal vein injection Latent infection (Parikka et al., 2012; van Leeuwen et al., 2015; Kiran et al., 2016)

  1. Small size requires less space; fast breeding makes it easy to access; transparent body makes it easy to observe the interaction between bacteria and host. Larvae can be a particularly good model for TB innate immunity, while adults can be used for research on both innate and acquired immunity

  2. Mycobacterium marinum has no biological safety risk for researchers, with shorter replication cycles (4 h) and shorter research periods

  3. Research on the dynamics of granuloma formation, granuloma could form early at the first week post-infection

  4. Stable LTBI, chronic, and active infection models could all be obtained by controlling the bacterial infection dosage

  5. Adult and larval zebrafish models complement one another in studying disease mechanisms, certain genetic mutations lead to opposite phenotypes in juvenile and adult zebrafish

  1. Could not be infected with standard strain H37Rv, but with Mycobacterium marinum

  2. Although the amino acid homology of Mycobacterium tuberculosis and M. marinum is close to 85%, the intracellular survival mechanisms are different and could not be reciprocally replaced

  3. Lack of zebrafish immunological reagents and specific antibodies, so mechanistic research on immune molecules and cells is difficult to carry out. Transcriptome and sequencing is the only method to study the immune response.

  4. Lack of clinical symptoms and manifestation of TB; therefore, unable to mimic most forms of human TB

  1. Best model for bacterial virulence studies

  2. Evaluation of efficacy and toxicity of anti-tuberculosis compounds

  3. Good model for host susceptibility research

  4. Research on dynamics of granuloma formation

  5. Larvae can be a particularly good model for TB innate immunity, while adults can be used for research on both innate and acquired immunity