measles is a highly contagious acute viral disease characterized by high fever , malaise , coryza , conjunctivitis , cough , and a maculopapular rash ( griffin , 2007 ) .
patients with measles develop a severe and temporary immunosuppression , which is often accompanied by secondary bacterial infections ( griffin , 2007 ) . despite the availability of highly effective vaccines ,
measles - related deaths were estimated to be 164,000 worldwide in 2008 ( who , 2009 ) . the causative agent is measles virus ( mv ) , which belongs to the genus morbillivirus in the family paramyxoviridae . the virus particle is enveloped and contains a non - segmented negative - strand rna genome encoding six tandem linked genes , n , p / v / c , m , f , h , and l. the genome is encapsidated by the nucleocapsid ( n ) protein and associated with viral rna - dependent rna polymerases , forming a helical ribonucleoprotein complex ( rnp ) . on the envelope ,
the viral particle possesses two types of viral glycoprotein spikes , the hemagglutinin ( h ) and fusion ( f ) proteins ( griffin , 2007 ) .
the h protein is responsible for binding to cellular receptors on the target host cells , and plays a key role in the determination of host cell specificity ( tropism ) of mv ( yanagi et al . , 2009 ) .
binding of the h protein to a receptor triggers f protein - mediated membrane fusion between the virus envelope and the host cell plasma membrane , releasing the rnp into the cytoplasm . in cells infected with mv
, the h and f proteins are expressed on the cell surface and cause cell - to - cell fusion , producing syncytia .
therefore , the distribution pattern of its receptors is a key determinant of which cells become infected with mv ( yanagi et al . , 2009 ) .
the initial discovery of an mv receptor came in 1993 ( dorig et al . , 1993 ; naniche et al . ,
two independent studies indicated that the receptor molecule for mv is the human membrane cofactor protein ( mcp / cd46 ) , a central component of the complement system , which is expressed ubiquitously on all organs and tissues throughout the human body ( dorig et al .
these findings were highly welcomed from the viewpoint that mv causes a systemic infection . meanwhile , kobune et al .
( 1990 ) reported the isolation of lymphotropic mv strains , and subsequent studies indicated that these lymphotropic mv strains do not use mcp / cd46 as a receptor ( yanagi et al . , 2009 ) .
importantly , kobune s isolates exhibited a high virulence in experimentally infected monkeys , whereas mcp / cd46-using classical mv isolates caused no or mild disease in monkeys ( kobune et al . , 1990 , 1996 ; takeda et al . , 1998 ) .
hence , new two questions have arisen for mv researchers . what is the receptor for these lymphotropic strains ?
which strains are the real wild - type ( wt ) mv strains ? in 2000 , using kobune s isolates , another receptor was identified ( tatsuo et al . , 2000 ) .
this receptor is signaling lymphocyte activation molecule , also known as cd150 ( slam / cd150 ) , which is expressed on cells of the immune system ( tatsuo et al . , 2000 ) .
subsequent studies clarified that slam / cd150 is a receptor for wt mv strains circulating in patients , and that mcp / cd46 does not act as a receptor for wt mv strains ( yanagi et al . , 2009 ) .
mcp / cd46 acts as a receptor only for vaccine and some laboratory mv strains ( yanagi et al . , 2009 ) .
currently , it is clear that these mv strains have acquired the ability to use mcp / cd46 as an alternative receptor to grow in laboratory cell lines lacking slam / cd150 expression ( yanagi et al . , 2009 ) .
hence , it has become generally accepted that wt mv is a lymphotropic virus that specifically targets immune cells , similar to the case of human immunodeficiency virus ( hiv ) and human t cell lymphotropic virus type 1 ( htlv1 ) . in 2000 , a recombinant mv , ic323 , was generated based on kobune s first isolate ( takeda et al . , 2000 ) , and has greatly contributed to our understanding of the molecular bases for the pathogenesis of wt mv strains ( takeuchi et al . , 2005 ; de swart et al .
, 2007 ; devaux et al . , 2008 , 2011 ; leonard et al .
, 2008 ; nakatsu et al . , 2008 ; de vries et al . , 2010 ; ludlow et al . , 2010 ; mhlebach et al . , 2011 ;
2011 ) . at that time , only slam / cd150-positive cells were found to be susceptible to wt mv infections .
however , it remained difficult to make a final conclusion that slam / cd150 is the sole receptor for wt mv , because histopathological examinations of measles patients and monkeys infected with mv have revealed considerable levels of mv protein expression in the epithelia of various organs , and histopathological changes are also evident in these epithelia ( nii et al . , 1964 ; lightwood and nolan , 1970 ; olding - stenkvist and bjorvatn , 1976 ; moench et al . , 1988 ; craighead , 2000 ; figure 1 ) . in 2003
, primary cultures of human small airway epithelial cells ( saecs ) were shown to be susceptible to wt mv infection ( takeuchi et al . , 2003 ) .
upon mv infection , large syncytia developed in saecs via a slam - independent mechanism ( takeuchi et al . , 2003 ) . after searching many cell lines , several epithelial cell lines with high susceptibility to mv infection
( 2008 ) clearly demonstrated that wt mv infects epithelial cell lines that form tight junctions ( tjs ) using an unidentified receptor ( leonard et al . , 2008 ; tahara et al . ,
2008 ) . using these cells and recombinant ic323 expressing green fluorescent protein ( ic323-egfp ; takeda et al . ,
2000 ; hashimoto et al . , 2002 ) , a final answer was obtained for the receptor on epithelial cells .
two groups independently demonstrated that nectin4 , which is expressed at adherens junctions ( ajs ) , acts as a receptor for mv ( mhlebach et al .
interestingly , mv loses the ability to use either slam / cd150 or nectin4 when it possesses specific mutations in the h protein ( leonard et al . , 2008 ; tahara et al . , 2008 ;
nectin4-blind mv still infects slam / cd150-positive immune cells efficiently ( slam / cd150-tropic ) , and conversely , slam / cd150-blind mv infects nectin4-positive epithelial cells efficiently ( nectin4-tropic ; leonard et al . , 2008 ; tahara et al . , 2008 ; figure 2 ) . in this
regard , mv is intrinsically dual - tropic to immune cells and epithelial cells ( figure 2 ) .
measles virus antigen and histopathological changes in bronchiolar epithelial cells . at 11 days post - infection ,
a cynomolgus monkey experimentally infected with wt mv ic323 strain was subjected to the histopathological examination .
multinucleated cell were seen in the epithelial layer of the bronchiole with inflammatory infiltration of eosinophils and lymphocytes .
( b ) immunohistochemical double staining for the n protein of mv ( left , green ) and keratin ( center , red ) .
multinucleated epithelial giant cells showing positive staining for the n protein are present in the bronchiole ( right , yellow in merged images ) .
wt mv ( ic323 ) infects and produces syncytia in both slam - positive lymphoblastoid b95a and nectin4-positive epithelial ii-18 cells ( dual - tropic ) .
ic323 with an r533a mutation in the h protein fails to spread in b95a cells ( slam - blind ) , but replicates well in ii-18 cells ( nectin4-tropic ) . on the contrary ,
ic323 with a y543s mutation in the h protein spreads in b95a cells ( slam - tropic ) , but fails to spread in ii-18 cells ( nectin4-blind ) .
there is now no doubt that slam / cd150 and nectin4 are the major receptors for mv .
however , other molecules may further support mv infection in vivo , being involved in the development of measles and its neurological sequela . for example
, the mechanism that the c - type lectin dc - specific intercellular adhesion molecule 3-grabbing non - integrin ( dc - sign ) acts as an attachment receptor for mv , thereby promoting mv infection of dcs , may be ideal to understand the extraordinarily high transmissibility of measles ( de witte et al .
it is well known that mv causes subacute sclerosing panencephalitis ( sspe ) , a persistent infection of the central nervous system ( cns ) with mv .
this occurs with a mean latency period of 710  years after suffering from acute measles at a frequency of 1/5,0001/100,000 reported cases of acute measles ( takasu et al . , 2003 ; bellini et al . ,
although nectin4 is a possible candidate for an mv receptor in the cns , no ( or undetectable ) nectin4 expression was observed in the cns in humans ( reymond et al . , 2001 ; brancati et al . , 2010 ) , and some mv strains derived from sspe patients are likely to use nectin4 inefficiently ( seki et al . , 2011 ) .
( 2007 ) suggest that neurokinin-1 , a substance p receptor , supports trans - synaptic transmission of mv by acting as a receptor for the f protein .
measles virus infection causes immunosuppression in patients and is often accompanied by secondary bacterial infections .
typically , mv - induced immunosuppression is characterized by a marked lymphopenia , and an early th1 response followed by predominant and prolonged th2 response in patients , with suppression of mitogen - induced lymphocyte proliferation ex vivo ( griffin and ward , 1993 ; schneider - schaulies and schneider - schaulies , 2009 ) . some , if not all , of these immunological observations must be attributed either directly or indirectly to the fact that mv uses slam / cd150 as a receptor .
slam / cd150 is a member of the slam - family receptors , which belong to the immunoglobulin ( ig ) superfamily ( veillette , 2010 ; ma and deenick , 2011 ) .
the slam - family consists of nine members ( cannons et al . , 2011 ; ma and deenick , 2011 ) .
the slam - family receptors are type i transmembrane proteins that typically possess an extracellular region with two ig - like domains ( an amino - terminal variable ( v)-like domain and a carboxy - terminal constant-2 ( c2)-like domain ) , a transmembrane region , and a cytoplasmic region that harbors multiple tyrosine - based motifs ( detre et al . , 2010 ; veillette , 2010 ; cannons et al . , 2011 ; ma and deenick , 2011 ) .
these motifs are referred to as immunoreceptor tyrosine - based switch motifs ( itsms ; cannons et al . , 2011 ) .
the slam - family receptors are expressed in a broad range of immune cells and play critical roles in immunity . in general , the receptors act as self - ligands and their homophilic trans - interactions occur between either heterotypic or homotypic immune cells ( veillette , 2010 ; ma and deenick , 2011 ) .
slam / cd150 is expressed on thymocytes , subsets of b and t lymphocytes , mature dendritic cells ( dcs ) , macrophages , and platelets , and their expression is upregulated or induced in lymphocytes and monocytes upon activation ( detre et al .
signaling lymphocyte activation molecule - associated protein ( sap)-family adaptors [ sap , ewing s sarcoma - associated transcript ( eat)-2 , and eat-2-related transducer ( ert ) ] play important roles for the signal transductions mediated by the slam - family receptors ( veillette , 2010 ; ma and deenick , 2011 ) .
they are small proteins that consist of a single src homology 2 ( sh2 ) domain and a short carboxy - terminal region .
sap associates intracellularly with the itsms in the cytoplasmic region of the slam - family receptors via the sh2 domain ( dong and veillette , 2010 ; veillette , 2010 ; ma and deenick , 2011 ) .
sap has the ability to bind concomitantly to the src - family protein tyrosine kinase , fyn , thereby coupling the slam - family receptors with fyn ( dong and veillette , 2010 ; veillette , 2010 ; cannons et al . , 2011 ) . thereafter ,
fyn phosphorylates tyrosine residues at the cytoplasmic region of slam - family receptors and other intracellular effector molecules , activating the downstream signals ( detre et al . , 2010 ; dong and veillette , 2010 ; cannons et al .
sap binding to the sh2 domain of slam - family receptors competes with the binding of other sh2 domain - containing molecules , thus modulating the slam - mediated signaling ( dong and veillette , 2010 ; veillette , 2010 ; cannons et al .
via slam / cd150-sap  fyn interactions play important roles in regulating t cell receptor - mediated induction of th2 cytokines , such as interleukin ( il)-4 and il-13 ( detre et al .
, 2010 ; cannons et al . , 2011 ; ma and deenick , 2011 ) .
eat-2 also mediates the signal transduction cascades of the slam - family receptors via a similar but distinct mechanism to that of sap ( cannons et al . , 2011 ) .
similar to sap , eat-2 also associates with the itsms of slam - family receptors through its sh2 domain , but mediates the subsequent signal cascades via its own phosphorylated tyrosine in the short carboxy - terminal region ( veillette , 2010 ) . in general
, the signals mediated by the sap - family adaptors induce the activation and differentiation of immune cells ( veillette , 2010 ) .
however , if the sap - family adaptors are absent , the slam - family receptors mediate inhibitory signals to immune cells ( a switch - of - function effect ; dong and veillette , 2010 ; veillette , 2010 ) .
roles for slam / cd150 in macrophage functions , cell adhesion , and nkt cell development have also been demonstrated , although many data were obtained in mice ( dong and veillette , 2010 ; veillette , 2010 ; cannons et al . , 2011 ; ma and deenick , 2011 ) .
x - linked lymphoproliferative syndrome is a rare immunodeficiency disease typically caused by mutations in the sap - encoding gene , sh2d1a ( veillette , 2010 ; ma and deenick , 2011 ) . patients with this syndrome have various functional defects and impaired differentiation of immune cells , indicating crucial roles for sap in normal immunity ( dong and veillette , 2010 ) .
barr virus infection are characteristics of the disease ( veillette , 2010 ; ma and deenick , 2011 ) .
although slam - family receptors have some functional redundancy , each receptor plays specific roles in a variety of immune responses ( dong and veillette , 2010 ; veillette , 2010 ) .
in general , lymphotropic viruses , such as hiv and htlv1 , can never be airborne , and are transmitted inefficiently even through direct contact with patients . in sharp contrast , mv transmits via aerosols , and has a highly contagious nature .
therefore , this transmission style of mv can not be easily explained by the fact that the virus uses a lymphocytic molecule , slam / cd150 , as a receptor .
the recent findings showing that mv uses nectin4 , a cell adhesion molecule ( cam ) expressed at the ajs of epithelia , may partly but nicely explain how and why mv transmits efficiently from a patient to other individuals .
epithelial cells are connected with one another through the formation of several specialized cell  cell junctions , such as tjs , ajs , desmosomes , and gap junctions .
tjs function as a physical barrier that prevents the passage of soluble molecules through the intercellular gaps , and also blocks the lateral movement of lipids and membrane proteins across the tj barrier , thereby acting as the border of the apical and basolateral membranes .
nectin4 is a member of the nectin family , which consists of four members ( nectin1 , 2 , 3 , and 4 ; takai et al . ,
nectin1 and nectin2 were originally identified as poliovirus receptor - related protein ( prr)-1 and prr-2 , respectively , and subsequently shown to support the entry of some herpes viruses ( takai et al .
are also type i transmembrane proteins that belong to the ig superfamily ( takai et al .
, they possess an extracellular region with three ig - like domains ( an amino - terminal v - like domain and two c - like domains ) , a transmembrane region , and a cytoplasmic region with a short afadin - binding motif ( takai et al .
the consensus motif was reported to be e / a - x - y - v for nectin1 , 2 , and 3 , while nectin4 does not have this motif but still binds to afadin ( reymond et al . , 2001 ;
( 2001 ) proposed a new consensus motif , k / r - x - x - y / l - v , for all four nectins .
afadin is an actin filament ( f - actin)-binding protein , and supports nectins to interact and co - operate with cadherins , other cams , and intracellular signaling molecules ( takai et al . ,
nectins are expressed as dimers , and interact in trans with other nectin dimers expressed on neighboring cells ( takai et al .
all nectins show homophilic interactions , while heterophilic interactions are also observed between specific nectins , such as those between nectin1/nectin3 and nectin 2/nectin3 ( takai et al .
nectin4 shows homophilic interactions as well as heterophilic interactions with nectin1 ( reymond et al . , 2001 ;
the ig v - like domain is used for the trans - interaction ( reymond et al . , 2001 ; fabre et al . , 2002 ) .
nectins play key roles in the initiation of aj formation , and regulate various physiological functions of epithelial cells , such as contact inhibition of cell movement and proliferation , survival , differentiation , and cell polarization ( takai et al . , 2008a , b ) .
although nectin1 and nectin2 are expressed in a broad range of tissues , the expression of nectin3 and nectin4 is more specific ( reymond et al . , 2001 ) .
( 2010 ) showed that human nectin4 is expressed mainly in the placenta and to lesser extents in the trachea , prostate , lung , and stomach .
( 2010 ) demonstrated nectin4 expression in human keratinocytes , suprabasal nucleated layers of the epidermis , and non - keratinized structures of hair .
some levels of expression in epithelial cells of the tonsil , oral mucosa , esophagus , and nasopharynx have also been reported ( www.proteinatlas.org ) .
although , in many cases , nectin4 is expressed in low or undetectable levels in normal human tissues , many cancer cells are highly positive for nectin4 .
thus , it has been proposed that nectin4 is a new tumor - associated marker ( fabre - lafay et al .
these observations may provide a rationale for the use of mv as an oncolytic agent ( mhlebach et al . , 2011 ) . in humans , mutations in the pvrl4 gene encoding nectin4
cause ectodermal - dysplasia - syndactyly syndrome ( edss ) , in which patients have affected skin and skin appendages , such as hair , teeth , and nails ( brancati et al . , 2010 ; jelani et al . , 2011 ) .
the pathology of measles can now be drawn with these two receptors ( figure 3 ) .
although nectin4-expressing epithelial cells can be the initial targets of mv , no or very limited infection of epithelia was observed in monkeys experimentally infected with mv at the early days after infection ( ludlow et al . , 2010 ; lemon et al . , 2011
instead , mv initiates its infection via slam - mediated entry into alveolar macrophages and dcs in the lung or respiratory tracts ( de witte et al . , 2008 ; de vries et al . , 2010
. these infections may allow mv to penetrate into the human body and reach the lymphoid organs or tissues , where slam / cd150-expressing cells are abundant ( corry et al .
after initial replication in these lymphoid organs or tissues , mv or mv - infected lymphocytes can easily enter the bloodstream .
subsequently , a dramatic mv infection is observed in all lymphoid organs , such as the spleen , thymus , appendix , tonsil , and lymph nodes , throughout the body ( moench et al .
, 1988 ; kobune et al . , 1996 ; de swart et al . , 2007 ; de vries et al . ,
2010 ) . at the time when the mv infection of lymphoid organs reaches its peak , mv infection of epithelia , such as squamous stratified epithelia of the tongue and buccal mucosa and ciliated epithelia of the trachea , becomes evident ( nii et al .
, 1964 ; olding - stenkvist and bjorvatn , 1976 ; moench et al . , 1988 ;
this epithelial infection is probably led by mv - infected immune cells and initiated through the basolateral side , since monkeys infected with mv often show infectious foci in the epithelia with mv - infected lymphoid or myeloid cells in the subepithelial cell layers of the trachea , bronchus , and tongue ( de vries et al . , 2010 ; ludlow et al . ,
the h protein expressed on mv - infected immune cells that migrate through the epithelial cell layer likely recognizes nectin4 expressed at ajs , triggering f protein - mediated membrane fusion between the mv - infected immune cells and the target epithelial cells .
( 2011 ) demonstrated a correlation between nectin4 expression and mv infection in epithelia in vivo .
importantly , mv has a mechanism that further facilitates virus shedding in the airway . in epithelia ,
mv selectively releases progeny virus particles from the apical membrane to the luminal side of the respiratory tract ( leonard et al . , 2008 ;
leonard et al . ( 2008 ) showed that mv genetically engineered to use slam / cd150 , but not nectin4 ( nectin4-blind or slam / cd150-tropic ) , does not shed progeny viruses into the respiratory tract , although it does show systemic infection of lymphoid organs , similar to the case for wt mv .
mv initiates its infection via slam - mediated entry into alveolar macrophages and dcs in the lung .
after initial replication in regional lymph nodes , mv enters the bloodstream and subsequently spreads to all lymphoid organs , such as the spleen , thymus , appendix , tonsil , and lymph nodes , throughout the body .
when the mv infection of the lymphoid organs reaches its peak , mv - infected immune cells transfer mv to epithelial cells through the basolateral side . at this step ,
mv uses nectin4 expressed at ajs as a receptor . in the epithelia , mv selectively releases its progeny virus particles from the apical membrane to the luminal side of the respiratory tract .
membrane cofactor protein / cd46 was first identified as a receptor for mv ( dorig et al . ,
however , our current knowledge of mv receptors has been totally transformed . in 2000 , it was shown that slam / cd150 expressed on cells of the immune system , but not mcp / cd46 , is a real receptor for wt mv .
however , recent studies further showed that slam / cd150 is not the sole receptor for mv .
mv has an intrinsic ability to enter not only immune cells but also epithelial cells . in 2011
, a clear answer was obtained through the identification of the epithelial mv receptor nectin4 , which is expressed at ajs , thereby partly explaining why mv exhibits its highly contagious nature ( mhlebach et al . , 2011 ; noyce et al . ,
however , many aspects and molecular mechanisms underlying immunosuppressive effects and a highly contagious nature of mv still remain to be elucidated .
analyses of physiological roles of mv receptors , slam / cd150 , and nectin4 , would provide deep insights into mv pathogenesis .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 measles is a highly contagious disease that causes temporary and severe immunosuppression in patients . signaling lymphocyte activation molecule ( slam ) expressed on cells of the immune system functions as a receptor for measles virus ( mv ) . 
 in addition to slam , vaccine strains of mv also use a ubiquitously expressed complement regulatory protein , cd46 , as a receptor , whereas wild - type ( wt ) mv strains do not use this receptor . 
 however , recent studies have indicated that slam is not the sole receptor for wt mv strains . 
 these strains have an intrinsic ability to enter both immune and epithelial cells using distinct receptor binding sites in their hemagglutinin ( h ) protein . 
 recently , a clear answer was obtained through the identification of an epithelial mv receptor , nectin4 , expressed at adherens junctions , thereby greatly improving our knowledge of mv receptors . 
 it is now clear that mv specifically targets two cell types , immune cells and epithelial cells , using slam and nectin4 , respectively . 
 mv loses the ability to use either slam or nectin4 when it possesses specific mutations in the h protein . however , nectin4-blind mv still infects slam - positive immune cells efficiently ( slam - tropic ) , and conversely , slam - blind mv infects nectin4-positive epithelial cells efficiently ( nectin4-tropic ) . in this 
 regard , mv is intrinsically dual - tropic to immune cells and epithelial cells . 
 although many aspects and molecular mechanisms underlying immunosuppressive effects and a highly contagious nature of mv still remain to be elucidated , analyses of physiological functions of these two receptors would provide deep insights into mv pathogenesis . 
Measles Virus
Discoveries of Cellular Receptors for MV
SLAM/CD150
Nectin4
Relevance of SLAM/CD150 and Nectin4 to MV Pathogenesis
Concluding Remarks
Conflict of Interest Statement