Editing Leptospirosis (section)

==Pathogenesis==
[[File:Pathogeneis of leptospirosis.svg|thumb|upright=1.3|alt= Diagram showing the pathogenesis of leptospirosis | Ways of ''Leptospira'' bacteria infecting human cells and blood stream.]]
The pathogenesis of leptospirosis remains poorly understood despite research efforts.<ref name="Karpagm2020"/><ref name="Kin Chin 2019">{{cite journal | vauthors = Chin VK, Basir R, Nordin SA, Abdullah M, Sekawi Z | title = Pathology and Host Immune Evasion During Human Leptospirosis: a Review | journal = International Microbiology | pages = 127–136 | date = March 2019 | volume = 23 | issue = 2 | pmid = 30875033 | doi = 10.1007/s10123-019-00067-3 | s2cid = 78095369 }}</ref> The bacteria enter the human body through either breaches in the skin or the mucous membrane, then into the bloodstream. The bacteria later attach to the [[Endothelium|endothelial]] cells of the blood vessels and [[extracellular matrix]] (complex network of proteins and carbohydrates present between cells). The bacteria use their flagella for moving between cell layers. They bind to cells such as [[fibroblast]]s, [[macrophage]]s, endothelial cells, and kidney epithelial cells.<!-- <ref name=Picardeau2017/> --> They also bind to several human proteins such as complement proteins, [[thrombin]], [[fibrinogen]], and [[plasminogen]] using surface leptospiral [[Immunoglobulin superfamily|immunoglobulin-like]] (Lig) proteins such as LigB and LipL32, whose genes are found in all pathogenic species.<ref name=Picardeau2017/><ref name="Kin Chin 2019"/>

Through [[innate immune system]], endothelial cells of the capillaries in the human body are activated by the presence of these bacteria. The endothelial cells produce [[cytokines]] and [[antimicrobial peptides]] against the bacteria. These products regulate the [[Coagulation#Coagulation cascade|coagulation cascade]] and movements of white blood cells.<ref name=Picardeau2017/> Macrophages presented in humans are able to [[Phagocytose|engulf]] ''Leptospira''. However, ''Leptospira'' are able to reside and proliferate in the [[Cytosol|cytoplasmic matrix]] after being ingested by macrophages.<ref name=Picardeau2017/> Those with severe leptospirosis can experience a high level of cytokines such as [[interleukin 6]], [[tumor necrosis factor alpha]] (TNF-α), and [[interleukin 10]]. The high level of cytokines causes [[sepsis]]-like symptoms which is life-threatening instead of helping to fight against the infection.<ref name="Cagliero 2018"/> Those who have a high risk of sepsis during a leptospirosis infection are found to have the [[HLA-DQ6]] [[genotype]], possibly due to [[superantigen]] activation, which damages bodily organs.<ref name="Haake 2015"/>

[[Humoral immunity]] is the [[Portal:Main|main]] immune response against the ''Leptospira'' cells. Agglutinating antibodies such as [[immunoglobulin M]] and [[immunoglobulin G]] are produced against the bacteria. Such antibodies are mainly directed against the [[Lipopolysaccharide|LPS]].<ref name="Kin Chin 2019"/>  ''Leptospira'' LPS only activates [[toll-like receptor 2]] (TLR2) in [[monocyte]]s in humans. The lipid A molecule of the bacteria is not recognised by human [[TLR4]] receptors. Therefore, the lack of ''Leptospira'' recognition by TLR4 receptors probably contributes to the leptospirosis disease process in humans.<ref name=Picardeau2017/>

Although there are various mechanisms in the human body to fight against the bacteria, ''Leptospira'' is well adapted to such an inflammatory condition created by it.<!-- <ref name=Picardeau2017/> --> In the bloodstream, it can activate host plasminogen to become [[plasmin]] that breaks down extracellular matrix, degrades [[fibrin]] clots and complemental proteins ([[C3b]] and [[Complement component 5|C5]]) to avoid [[opsonisation]]. It can also recruit complement regulators such as [[Factor H]], [[Complement component 4B|C4b]]-binding protein, factor H-like binding protein, and [[vitronectin]] to prevent the activation of [[Complement membrane attack complex|membrane attack complex]] on its surface. It also secretes [[protease]]s to degrade complement proteins such as [[Complement component 3|C3]]. It can bind to thrombin that decreases the fibrin formation. Reduced fibrin formation increases the risk of bleeding.<ref name=Picardeau2017/> ''Leptospira'' also secretes [[sphingomyelinase]] and [[haemolysin]] that target red blood cells.<ref name="Karpagm2020"/>

''Leptospira'' spreads rapidly to all organs through the bloodstream.<ref name=Picardeau2017/> They mainly affect the liver. They invade spaces between [[hepatocyte]]s, causing apoptosis. The damaged hepatocytes and hepatocyte intercellular junctions cause leakage of bile into the bloodstream, causing elevated levels of [[bilirubin]], resulting in jaundice. Congested [[liver sinusoid]]s and [[perisinusoidal space]]s have been reported. Meanwhile, in the lungs, petechiae or frank [[Haemorrhage|bleeding]] can be found at the [[alveolar septum]] and spaces between alveoli.<ref name="Haake 2015"/> ''Leptospira'' secretes toxins that cause mild to severe kidney failure or [[interstitial nephritis]].<ref name="Kin Chin 2019"/> The kidney failure can recover completely or lead to [[atrophy]] and [[fibrosis]].<ref name="Haake 2015"/> Inflammation of the heart muscles, coronary arteries, and [[aorta]] is rare.<ref name="Bennett 2015"/>