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Alveolar macrophage is the primary cell type involved in the initial uptake of Mtb, after

that dendritic cells and macrophages also come and take part in the phagocytosis

process, mediating the subsequent host signaling to eliminate bacterial infection. The

initial recognition and uptake of Mtb require a number of pathogen recognition

receptors on the membrane of innate immune cell types, which either recognize Mtb

directly via pathogen associated molecular patterns (PAMPs) or indirectly via opsonin

with immunoglobin G (IgG) or complement on the bacterial surface. Mtb is an

intracellular bacterium that can survive and multiply within macrophages, therefore the

initial recognition and uptake is also exploited by Mtb for its entry into the cells and

establishing infection. Below is a summary of surface receptors involved in the uptake

of Mtb. It remains unclear whether different modes of entry into macrophage may lead

a. Complement receptors

The complement system comprises a number of soluble proteins that respond in a

sequential manner, producing a cascade of reactions. The complement protein can be

classically activated by its binding to an antigen-antibody complex or alternatively

activated without antigen-antibody complex. The activated complement functions

opsonizating pathogens to facilitate their phagocytosis, through chemotaxis to attract the

phagocytes, or through lysis of antibody-coated bacteria. Macrophages possess various

receptors for complement on their cell surface, including complement receptor (CR) 1,

CR3 and CR4. Among CRs, CR3 is the principal receptor which is expressed

dominantly on monocytes, macrophages, neutrophils, and natural killers.

Mtb is able to activate the complement system through the alternative pathway, resulting in the opsonization of bacteria. The opsonized Mtb then can bind to CRs and

be phagocytosed in the phagosome. The role of CRs on macrophages in the course of

Mtb infection has been debated. Many works indicate that lack of or blocking of CR3 results in the reduced phagocytosis of Mtb85,86; whereas other studies have shown that

antibody blocking of CR3 has no effect on the binding of Mtb87, the induction of anti-

microbial effector mechanism or bacterial survival in macrophages86. Additionally,

CR3-deficient mice have exhibited no defects in the control of Mtb infection compared

to wild type88.

b. C-type lectin receptors

C-type lectin receptors (CTLRs) consist of carbohydrate-binding C-type domains that

can recognize and bind to carbohydrate-rich molecules. In addition to participating in

various processes such as cell adhesion and migration or lipid scavenging, CTLRs

Mtb is recognized by a number of transmembrane CTLRs including mannose receptor (MR), Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin

(DC-SIGN), MINCLE, and DECTIN-1. MR can be found on most types of tissue

macrophages but not on circulating monocytes90. DC-SIGN is expressed mainly on the

surface of dendritic cells (DCs) but also on the macrophage surface. These receptors are

reported to bind lipoarabinomannan (LAM)91 or mannose-capped LAM (ManLAM)92,

components on Mtb cell wall, to induce the bacterial phagocytosis. The binding of LAM

or ManLAM are also reported to inhibit the phagosome-lysosome fusion in the infected

macrophage92, prevent the T cell-mediated immune response by inhibiting the

maturation of infected DCs, and induce the production of anti-inflammatory cytokine

IL-1093. These conditions promote host immunosuppression and may contribute to Mtb

survival.

c. Scavenger receptors

Scavenger receptors (SRs) comprise a large family of integral membrane proteins

belonging to at least 8 different subclasses (A-H) based on their tertiary structure94,95.

These receptors are known to bind a variety of ligands including modified or oxidised

low-density lipoproteins, apoptotic cells and pathogens94.

Both class A including scavenger A (SRA) and macrophage receptor with collagenous

structure (MARCO), and class B SRs are involved in Mtb recognition and uptake. Many

studies have indicated that these SRs participate in phagocytosis of mycobacterial

species, including M. leprae96, M. avium97, M. bovis BCG98, and Mtb87,99 and are

required for production of pro-inflammatory cytokines against mycobacterial infection.

after CR and MR are blocked87. This also leads to a reduction in TNF-α production

mediated by mycobacterial lipopeptides100,101.

d. Fcγ receptors

There are two types of Fcγ receptors (FcγRs), including activation receptors and inhibitory receptors that contain an immunoreceptor tyrosine activating motif or

inhibitory motif, respectively. While DCs and macrophages express both activating and

inhibitory receptors, natural killer (NK) cells only express activating FcγRs and B cells are limited to inhibitory FcγRs. All FcγRs mediate the internalization but the type of receptors will determine the subsequent processes. The internalization by activating

FcγRs favors effector responses for antigen processing and presentation that results in activation of T cells, while the internalization by inhibitory FcγRs favors preserving the

intact antigen for presenting to B cells102.

The uptake of Mtb opsonized with antibody against TB via FcγRs is shown to lead to a

rapid phagosome-lysosome fusion103, an enhanced oxidative burst and production of

pro-inflammatory cytokine in infected macrophages104. There is no difference in the

intracellular growth rate after internalization between opsonized and non-opsonized

tubercule bacilli, indicating that entry by FcγRs or alternative does not affect the intracellular survival of bacteria103.

e. Toll like receptors

Toll like receptors (TLRs) are transmembrane proteins with an extracellular leucine-rich

domain to recognize bacterial products. TLRs that are known to be involved in Mtb

recognition include TLR2, TLR4, TLR9 and possible TLR836. TLR2 can recognize a

number of lipoglucans and lipids on mycobacterial cell walls, including LAM, LAM-

to recognize different bacterial structures could be explained by the unique ability of

TLR2 to cooperate with is co-receptors including TLR1, TLR6, CD14, or CD36105,106.

Treatment of mice macrophages with PIM, LAM or LM leads to an increased

production of pro-inflammatory cytokines107. TLR4, a receptor in concert with CD14

binding to LPS of Gram negative bacteria, recognizes Mtb cell wall lipids,

glycoproteins, and secreted proteins108. The intracellular TLR9 that is located on the

phagosomal membrane can recognize Mtb DNA and induce TNF-α production109. The

significant role of TLRs in TB infection is not always consistent in vivo. TLR2 and

TLR4 are demonstrated to be required for the control of Mtb infection in mice110,111 but

other studies have shown the unnecessary role of these receptors in immunity against

Mtb infection112,113. Nevertheless, many genetic studies have shown the association of

polymorphisms in TLR genes and TB susceptibility114.

f. Other receptors

In addition to these important receptors, other receptors and proteins can recognize and

mediate the interaction of innate immune cells and Mtb. Surfactant proteins A in the

lung can coat Mtb, enhancing macrophage binding and Mtb uptake by binding to

surfactant protein A receptors on the macrophage115 or to other receptors such as FcγRs,

complement receptors116, and probably mannose receptors117. CD14 can also recognize

and bind Mtb via LAM118 and chaperonin 60.1119, which mediate the bacilli

internalization of macrophages120.