doi:10.5455/vetworld.2013.118-121 Neutrophils in tuberculosis: will code be unlocked?

Tuberculosis is a devastating disease throughout the world both in humans and animals. Its history is vast, which dates back to era of Robert Koch. There is a huge amount of immunological studies in the aspect of tuberculosis but there remain many unanswered questions. Neutrophils, cells of First line defence are being neglected in tuberculosis. Macrophages are considered as the key player in case of tuberculosis. Researches reveal that neutrophils play some interesting roles; it can be called as a bi-directional weapon. It plays instrumental role in killing mycobacterium, recruiting macrophages and also works hand in hand with macrophages in order halt the spread of the organism. Neutrophils also activates innate immunity, secretes some substances like ectosomes, which favour in trapping the mycobacterial organisms. Whether neutrophils drills the mycobacterium or gets succumbed to it depends on the stage of infection. Neutrophils at times act like a suicidal bomber, by carrying the organisms to different organs and spreading the infections. In chronic cases they are also implicated to granuloma formation, the classic sign of TB.


Facts about neutrophils
Mycobacterium tuberculosis spares no one Neutrophils kill organism both by oxidative (phathroughout the world and when it is unleashed it lashes gocytic) and non oxidative (degranulation) [5].There more than 4000 people /day (WHO report 2010 -global are 3 types of granules seen in neutrophils.They are: tuberculosis control).Days are growing fast since the * Azurophilic granules (or "primary granules")-contains start of the research in Tuberculosis (TB) but the proteins like myeloperoxidase, bactericidal/ susceptibility to infection remains unanswered.The permeability-increasing protein (BPI), defensins, consequence of the TB ranges from early, asymptoand the serine proteases neutrophil elastase.matic clearance through latent infection to clinical * Specific granules (or "secondary granules")disease [1].Whenever there is talk about immunity in contains lactoferrin and cathelicidin.case of TB, macrophages are the first thing that comes * Tertiary granules -contains cathepsin and gelatinase.to our mind and not neutrophils, though the later is the Neutrophils in TB: two way traffic?first line of defence in the body.
Neutrophil contribute to the early defence against

Neglected neutrophils
mycobacteria.The scientific community is split, Neutrophils are the poorly ranked components of regarding the action of neutrophils in TB.LPS used to the host defence in case of TB.The reason behind this recruit neutrophils to the lungs of rat during airborne low profile chapter of neutrophils is because of the infection with 200 M.tuberculosis, decreases downinherent difficulties in working with these cells.The stream colony forming units in lung [6].Depleting key hurdles for neutrophils are: granulocytes in mice before intra tracheal infection 1) they are short lived 5 with 10 organisms, increases the number of colony 2) easily activated forming units downstream in lung and spleen [7].3) cannot be cryopreserved [1].
Science is not always constant and consistent.On the Hence in-vitro study is not feasible.
other side some works proved negative to the above Newer concepts of neutrophils in TB mentioned action of neutrophils in TB.For example: 6 no effect on bacterial load in mice with 10 colony * Neutrophils are the commonly affected phagocyte forming unit of M.tuberculosis, M.bovis, BCG or M. in human TB [2].
fortuitum in case of granulocyte depletion [8].Murine * Neutrophils significantly contribute to control of experiments with RB6-8C5 monoclonal antibodies to TB in human blood [3].
deplete granulocyte receptor positive cells, in addition * Interferon in human whole blood which was to the target (Ly6G antigen) on neutrophils, it also neutrophil driven contributes to disease pathotarget Ly6C on plasmocytoid dendritic cells, monogenesis [4].
cytes [9].The stage of infection plays a crucial role: in the body.Thus playing the role of "granulocytic Trojan established TB disease, higher neutrophil counts are Horse" [21].Mice treated with anti IL17 during M.tuberculosis infection shows 100 fold decrease in associated with poor prognosis [10] M.smegmatis and M.tuberculosis fail to fuse to Neutrophil recruitment occurs at the site mycoazurophil granules [24].lysX gene of M.tuberculosis bacterial infection.Recruitment occurs at the perivascular is same as mprF gene of Staphylococcus aureus that sites within an hour when intra-venous infection with increase the lysine content of membrane lipids, hence M.tuberculosis [11].There is infiltration of neutrophils negative charge is decreased and susceptibility to HNP in liver within 2 hours of systemic challenge with also reduced [25].

M.avium [12]. There is skin infiltration of neutrophils
Macrophages seem to take up free HNP and this within 3 hours of BCG infection in rabbits [13].In case increases their ability to kill mcobacteria [26].Phagoof mice it takes 4 hours for skin infiltration with the cytosis of apoptotic neutrophils by macrophages same challenge study as that of rabbit [14].

Mechanism of recruitment: In sensitized animals there
Neutrophil-macrophage co-operation is a powerful immune response to mycobacterial Clearing of cytotoxic, short lived neutrophils are challenge [11] Factor (TNF) [30].Sometimes the reverse may happen; The mechanisms which cause this interaction are: ingestion of apoptotic cell with pathogen may result in 1) Direct recognition 2) Opsonisation.
pro inflammatory effect [30].This may be due to 1) Direct recognition: Pattern Recognition Receptors expression of heat shock proteins [31] or activation of makes this interaction possible [18].Toll Like macrophages by neutrophil proteases.Receptor 2 (TLR2) also involved in this interaction.
Phagocytosis of apoptotic cell may produce anti/pro There is impaired control of M.tuberculosis and M.
inflammatory effect based on the mycobacteria inside avium infection in TLR2 deficient mice [12].Lipothe neutrophil is alive or dead.If the organism is killed, arabinomannan or 19 kDa lipoprotein of mycobateria there is anti-inflammatory effect.If the organism is is the ligand for TLR2.Blocking TLR4 reduces IL8 living it causes pro-inflammatory effect.production, in response to infection [19].Hence TLR4 Effect of neutrophils on acquired immunity may also be involved in this interaction between Neutrophils produce IL 12, macrophage inflammatory neutrophils and mycobecteria.
protein (MIP 1α) [32] which attract T lymphocytes and 2) Opsonisation: Apart from direct recognition, opsocause its maturity.Neutrophils can also produce IL 10 nisation seems to play a key role in the phagocytosis of which might limit acquired immunity [33].the mycobacteria by neutrophils.There is reduction in the ability of Ficoll isolated neutrophils to phagocytose granular anti microbial proteins form the NETs [34].This remains a controversial stuff.Theoretically Pro-inflammatory stimuli like IL8, TNFα forms NETs speaking the neutrophils kill and stop the infection at an [35].NETs can trap mycobacteria [36].NETs formed early stage.But in the absence of killing, the against mycobacterial infection are unable to kill neutrophils traffics the infection to different organs of mycobacteria instead it kills Listeria monocytogene
. number of organism in spleen[22].Treatment with

Process of apoptosis-pro inflammatory or anti infla-
[28]terleukin 17 (IL 17) and IL 23 carried out by macrophages.Macrophages are produced from T helper 17 (Th 17) cell are the key in attracted by the chemokines derived from neutrophil recruitment of neutrophils[15].IL 8 from macrophage[28].Macrophage chemotaxis is also stimulated by also plays a key role[16].In simpler terms we can say mycobacterial lipoarabinomannan[29].that the initial signal releases the inflammatory vivo.J. Immunol.179: 2509-2519.18. May, M.E.and Spagnuolo, P.J. (1987).Evidence for Conclusion activation of a respiratory burst in the interaction of human Neutrophils are seen in the early stages of the neutrophils with Mycobacterium tuberculosis.Infect.Immun.55: 2304-2307.mycobacterial infection.In chronic cases the same 19.Godaly, G. and Young, D.B. (2005).Mycobacterium bovis neutrophils may act in the pathology of granuloma bacilli Calmette Guerin infection of human neutrophils formation.Thus neutrophil act as a "Double edged induces CXCL8 secretion by MyD88-dependent TLR2 and Sword".The role of neutrophils in killing the myco-TLR4 activation.Cell Microbiol.7: 591-601.20.Majeed, M. et al. (1998).Roles of calcium and annexins in bacteria is still doubtful.It may disseminate the phagocytosis and elimination of an attenuated strain of organism to various organs by acting as a granulocytic Mycobacterium tuberculosis in human neutrophils.Microb.
in trojan horse.