TY  - CHAP
M1  - Book, Section
TI  - Tuberculosis Pathogenesis and Immunity
A1  - Raviglione, Mario C.
A2  - Jameson, J. Larry
A2  - Fauci, Anthony S.
A2  - Kasper, Dennis L.
A2  - Hauser, Stephen L.
A2  - Longo, Dan L.
A2  - Loscalzo, Joseph
PY  - 2018
T2  - Harrison's Principles of Internal Medicine, 20e
AB  - The  interaction  of  M.  tuberculosis  with  the  human  host  begins  when  droplet  nuclei  containing  viable  microorganisms,  propelled  into  the  air  by  infectious  patients,  are  inhaled  by  a  close  bystander.  Although  the  majority  of  inhaled  bacilli  are  trapped  in  the  upper  airways  and  expelled  by  ciliated  mucosal  cells,  a  fraction  (usually  <10%)  reach  the  alveoli,  a  unique  immunoregulatory  environment.  There,  alveolar  macrophages  that  have  not  yet  been  activated  (prototypic  alternatively  activated  macrophages)  phagocytose  the  bacilli.  Adhesion  of  mycobacteria  to  macrophages  results  largely  from  binding  of  the  bacterial  cell  wall  to  a  variety  of  macrophage  cell-surface  molecules,  including  complement  receptors,  the  mannose  receptor,  the  immunoglobulin  G  Fcγ  receptor,  and  type  A  scavenger  receptors.  Surfactants  may  also  play  a  role  in  the  early  phase  of  interaction  between  the  host  and  the  pathogen,  and  surfactant  protein  D  can  prevent  phagocytosis.  Phagocytosis  is  enhanced  by  complement  activation  leading  to  opsonization  of  bacilli  with  C3  activation  products  such  as  C3b  and  C3bi.  (Bacilli  are  resistant  to  complement-mediated  lysis.)  Binding  of  certain  receptors,  such  as  the  mannose  receptor,  regulates  postphagocytic  events  such  as  phagosome–lysosome  fusion  and  inflammatory  cytokine  production.  After  a  phagosome  forms,  the  survival  of  M.  tuberculosis  within  it  seems  to  depend  in  part  on  reduced  acidification  due  to  lack  of  assembly  of  a  complete  vesicular  proton-adenosine  triphosphatase.  A  complex  series  of  events  is  generated  by  the  bacterial  cell-wall  lipoglycan  lipoarabinomannan,  which  inhibits  the  intracellular  increase  of  Ca2+.  Thus,  the  Ca2+/calmodulin  pathway  (leading  to  phagosome–lysosome  fusion)  is  impaired,  and  the  bacilli  survive  within  the  phagosomes  by  blocking  fusion.  The  M.  tuberculosis  phagosome  inhibits  the  production  of  phosphatidylinositol  3-phosphate,  which  normally  earmarks  phagosomes  for  membrane  sorting  and  maturation  (including  phagolysosome  formation),  which  would  destroy  the  bacteria.  Bacterial  factors  block  the  host  defense  of  autophagy,  in  which  the  cell  sequesters  the  phagosome  in  a  double-membrane  vesicle  (autophagosome)  that  is  destined  to  fuse  with  lysosomes.  If  the  bacilli  are  successful  in  arresting  phagosome  maturation,  then  replication  begins  and  the  macrophage  eventually  ruptures  and  releases  its  bacillary  contents.  This  process  is  mediated  by  the  ESX-1  secretion  system  that  is  encoded  by  genes  contained  in  the  region  of  difference  1  (RD1).  Other  uninfected  phagocytic  cells  are  then  recruited  to  continue  the  infection  cycle  by  ingesting  dying  macrophages  and  their  bacillary  content,  thus,  in  turn,  becoming  infected  themselves  and  expanding  the  infection.  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/20
UR  - accesspharmacy.mhmedical.com/content.aspx?aid=1178426623
ER  -