infectious diseases caused by bacterial , viral , fungal , or parasitic 
 pathogens continue to be the leading cause of morbidity and 
 mortality worldwide despite the availability of effective 
 antimicrobial agents and vaccines over the last fifty years or more .
the continual emergence 
 of previously undescribed new pathogens , reemergence of old pathogens , and the 
 rising crisis of antibiotics resistance will certainly heighten the global impact of microbial infections in the 21st century .
these problems are mainly due to inadequate 
 knowledge of the dynamic duality relationships between symbiosis ( sym ) and 
 pathogenesis ( pat ) in microbial infections . the term symbiosis , which may 
 have many variations on its definition , in this paper refers to living together 
 through a close and prolonged association between two or more organisms of 
 different species [ 3 , 4 ] .
there are two major limitations inherent in the 
 conventional theories of microbial infection . on the one hand , in the 
 past century ,
focusing research on 
 individual virulence genes and the important pathogens has been the traditional 
 approach to human infectious diseases . on the other hand , as joshua lederberg pointed out [ 6 , 7 ] , medical science 
 is imbued with the manichaean view of the microbe - human host 
 relationship :  we good ; they evil .
 almost all broad - spectrum antimicrobial 
 agents , which are in the best interest of pharmaceutical industries , kill both 
 the good microbes as well as the bad germs . even though narrow - spectrum antiinfective 
 agents are not  narrow  for pathogens , they also target both the good and bad 
 microorganisms with a limited range of species .
animals and plants are continually infected by an extensive 
 diversity of symbiotic or invading organisms including bacteria , virus , fungus , 
 or parasites .
infection of bacteria by phages started long before the emergence 
 of animals and plants .
microbial infection is an evolutionary paradigm 
 which is associated with coevolution between hosts and microbes [ 6 , 7 , 9 ] .
this 
 coevolution can be defined as the process of reciprocal and dynamic genetic 
 changes in two or more species .
the conventional wisdom in medicine holds 
 that microbial infection is a pathogenic process in which a pathogen enters , 
 establishes itself , and multiplies in the host .
this represents  zero - sum 
 thinkingthe belief that if one player gains , other 
 player must inevitably lose .
methods and concepts of the zero - sum game theory 
 have proved successful in studying the strategy of pure conflict .
the most 
 challenging issue in infectious diseases is how to dissect the dynamic sym - pat 
 duality ( dspd ) in microbial infections using infectomics and mathematics such 
 as focal point- ( fp- ) based game theory .
game theory , defined in the broadest 
 sense , is the study of the strategies of conflict , cooperation , and mixed 
 situations in which both coexist .
thomas schelling 's concept of focal point , which is an equilibrium usually 
 standing out from the others , addressed the crucial question of how to 
 interpret the multiplicity of equilibria [ 11 , 12 ] .
focal point , the principal 
 component of schelling 's game theory , is a convergence point of expectations 
 about actions in a game .
this article attempts to enlarge the scope and 
 application of focal point game theory in microbial infections , extending from 
 the zero - sum games to the nonzero - sum games .
our health is associated with the dynamic interactions of 
 three microbial communities   ( nonpathogenic microbiota ( np ) , conditional 
 pathogens ( cp ) , and unconditional pathogens ( up ) ) with the hosts at three different 
 health statuses ( nonsusceptibility ( ns ) , conditional susceptibility ( cs ) , and 
 unconditional susceptibility ( us ) ) ( see figure 1 ) .
np is the major microbial 
 community which forms a healthy symbiotic  superorganism  with the hosts .
the 
 ecology and evolution of np - ns interaction are essential and fundamental for health . from 
 birth to death , we share a benign coexistence with a vast , 
 complex , and dynamic consortium of microbes .
most of our microbial commensals reside 
 in our gastrointestinal ( gi ) track packed with up to 100 trillion ( 10 ) 
 microbes [ 1 , 13 ] .
these include stimulating the immune system , protecting the host 
 from microbial invasion , and aiding digestion .
the gut microbiota , which is essential 
 for human homeostasis , is established rapidly after birth and remains 
 relatively stable throughout the life .
the gi mucosa provides a protective 
 interface between the internal environment and the constant external challenge 
 from food - derived antigens and microbes .
cp and up are minor microbial 
 communities that mainly contribute to the pathogenesis of microbial diseases .
the distinction between 
 the commensal and the pathogen in the cp community can be blurred because they 
 may cause diseases under certain sub - health conditions of the hosts , or in 
 immunocompromised hosts .
for example , pneumococcus , meningococcus , and 
 haemophilus bacteria regularly exist as part of the normal microbiota of the 
 host respiratory track and are mostly carried asymptomatically despite the fact 
 that they can cause well - defined diseases [ 14 , 15 ] .
microbes in the cp community dynamically evolve in two 
 opposite directions , which are toward either the np ( more cooperative or 
 mutualistic ) or up ( more pathogenic ) microbial community . microbes with high 
 pathogenicity belong to the up microbial community .
the three microbial 
 communities and three statuses of the hosts are subjected to dynamic reciprocal 
 changes driven by transfer of genetic materials . extending along the 
 dynamic continuum from conflict to cooperation
, microbial infections always 
 involve symbiosis and pathogenesis , which are two fundamental components of the 
 host - microbe interactions ( see figure 2 ) .
there exists a dynamic sym - pat 
 duality in microbial infection , which is the most fundamental issue of 
 infectomics .
dspd is reflected in the genotypic and phenotypic infectomes , 
 which are encoded by the genomes of both the microbes and their hosts .
the 
 opposition and unity of sym and pat are indispensable , and the academic 
 viewpoint that the unity of opposites of sym and pat gives impetus to the 
 development of microbial infection is considered as the core idea and radical 
 principle of the duality representations of microbial infections . in certain 
 circumstances and at a certain stage of the development of microbial infection , 
 each of the two aspects of sym and pat will transform from antagonism into 
 mutualism or from mutualism into antagonism .
sym and pat can be quantitated by 
 measuring symbiotic index ( si ) , which is quantitative fitness for the symbiotic 
 partnership , and pathogenic index ( pi ) , which is quantitative damage to the 
 symbiotic partnership , respectively .
the most crucial studies are to   identify 
 infectomic signatures specific for si and pi .
the set of symbiotic or 
 pathogenic parameters is defined as a function si(x ) or pi(x * ) .
si(x ) and pi(x * ) are continuous functions ranging 
 from 0 to 1 to admit different degrees of sym and pat , respectively .
si(x ) = 0 and pi(x * ) = 0 indicate that x 
 and x * are perceived to be zero - symbiotic and zero - pathogenic , respectively .
si(x ) = 1 and pi(x * ) = 1 indicate that x 
 and   x * are perceived to be completely symbiotic and completely pathogenic , respectively . 

intermediate values of si(x ) and pi(x * ) indicate that x 
 and x * are perceived to be partially symbiotic and partially pathogenic , 
 respectively .
symbiotic 
 points are used to determine the dynamic 
 duality between sym and pat .
the 
 symbiotic point ( sp ) is a function of si and pi : 
 ( 1)sp = f(si , pi ) . 

the focus of the dynamic duality research is to examine 
 the ability of sp to transform situations of potential conflict ( up - us and cp - cs ) into 
 situations of cooperation ( np - ns ) .
sp 
 bears analogy to schelling 's focal point , which is any feature of such a game 
 that provides a focus of convergence . in the games with multiple nash 
 equilibria
such an   equilibrium is a 
 focal point which can be easily recognized by all the players .
thomas 
 schelling 's strategy of conflict ( 1960 ) has been recognized as one of the most important works of game theory [ 11 , 17 ] .
there is no doubt that focal points play a central role in schelling 's 
 game theory .
understanding focal points is not only a key to improving game 
 theory but also a key to dissecting sps . in this paper ,
three types of gtms are proposed for studies on np - ns interactions 
 ( cooperative game ) , up - us interactions ( noncooperative games ) , and cp - cs 
 interactions ( dilemma or bargaining game ) . 

first , the ns - ns interactions are dissected with pure cooperative games 
 in which each player chooses the strategy corresponding with the focal point in 
 the expectation that the others will do the same .
the significance of focal 
 points can be shown most clearly in the pure cooperative games . as there is no 
 conflict of interests in these games , all the players merely want to cooperate 
 and they do not choose the alternative ways .
analysis of the cooperative game 
 issues is to focus on coalition formation and distribution of the gains through 
 cooperation .
the sp in the np - ns games tends to be maximal 
 ( see figure 2 ) .
secondly , noncooperative gtms are used for analysis of the up - us 
 interactions .
in contrast to cooperative games which focus on collective 
 rationality and common interest , noncooperative games emphasize individual 
 rationality and individual optimal strategy .
the sp in the up - us games tends to 
 be minimal ( see figure 2 ) . in games 
 of pure conflict
, defection is the equilibrium strategy and the total benefit 
 to all players in the game , for every combination of strategies , always adds to 
 zero ( zero - sum ) . in the antagonistic up - us interaction model , the surviving 
 strategies of the up community conflict with that of the us host .
the up 
 evolves to exploit the host as much as possible , and the host adapts to exclude 
 or limit the damage caused by the up .
thirdly , we consider the strategic 
 use of focal point theory in mixed situations to analyze the cp - cs interactions 
 in which there is both conflict and mutual dependence .
the most well - known 
 example is the prisoner 's dilemma game ( a two - player game ) in which each player 
 chooses between a cooperating and defecting strategy . in this game
the two - player game can 
 be extended to the n - player prisoner 's dilemma game with arbitrary numbers of 
 players .
e. coli is one of the best understood 
 and most thoroughly studied organisms and is advantageous as a model microorganism 
 for the current studies .
this bacterium is genotypically and phenotypically a 
 highly diverse species , which is present in the three microbial communities ( see 
 table 1 ) .
most e. coli strains are 
 commensals of higher vertebrates belonging to np , but some are pathogenic ( cp and up ) .
uropathogenic e. coli ( upec ) in the cp group are the 
 most common cause of community - acquired urinary tract infection ( uti ) .
upec are 
 responsible for about 80% of the estimated 150 million utis diagnosed annually 
 .
e. coli o157 , which belong to 
 the up group , is a major food pathogen .
shigella species , the cause of 
 dysentery , are now known to be multiple distinct lineages of e. coli .
genomes of those e. coli strains have been sequenced ( see 
 table 1 ) . recently ,  better 
e. coli strains 
 ( mds41 , 42 , 43 ) have been engineered in which about 15% of the genome has been 
 removed with the use of synthetic biology .
coliphage , a virus which 
 infects e. coli , is a major 
 contributor responsible for diversification of e. coli [ 20 , 21 ] . from a population - dynamic view , the interactions 
 between coliphage and e. coli are 
 analogous to those of a predator and a prey .
the development of microbial infections depends 
 on the dynamic sym - pat duality , which is governed by the genomes of both 
 the microbes and their hosts .
molecular 
 evolution of genetic structures for the sym - pat duality is influenced by both 
 biotic and abiotic environmental factors in the ecosystems .
there are three 
 types of genetic / genomic determinants ( ggds ) that may contribute to the sym - pat 
 duality of microbial infections under specific environmental conditions ( see figure 3 ) .
the sym 
 ggds from the microbial partner include symbiosis - related genomic islands 
 ( syi ) , plasmids , transposons , and microbiome , which is a collective genome of 
 microbiota [ 2 , 22 , 23 ] .
the 
 symbiotic homeostasis of the superorganism formed by the microbiota and its 
 host is governed by hologenome , a complex of the host genome and microbiome [ 22 , 25 ] .
these include pathogenicity islands ( pai ) , virulence plasmids , 
 pathogen - associated molecular patterns ( pamps ) , and endogenous alarmins .
pamps are a diverse group of microbial 
 molecules , which are recognized by the host innate and adaptive immune system , primarily 
 through toll - like receptors ( tlrs ) .
effector cells of the innate and adaptive immunity can 
 release alarmins when they are activated by pamps .
endogenous alarmins and 
 exogenous pamps elicit similar responses by conveying a similar message . 

therefore , they constitute a larger family of damage - associated molecular 
 patterns ( damps ) .
the third type of ggd pool has dual functions that depend on 
 external and internal environments .
these include ecological islands ( eci ) , 
 certain ggds from conditional pathogens ( such as cp factors ( cpfs ) and cp 
 islands ( cpis ) ) , and the host ggds with dual effects on microbial infections .
the 
 dual ggds contribute to the sym and pat duality in specific ecological niches 
 and within particular organisms .
the same ggd may act as an syi when the 
 microbial recipient establishes a symbiotic relationship with its host , but 
 becomes a pai when it is adapting the pathogenic niche .
a comparative infectomic 
 study suggests that gima , a 20-kb genomic island , is a typical cpi .
the 
 dual biological functions of gima depend on the genomic environments in e. coli strains .
gima present in 
 meningitic e. coli k1 genome 
 ( o18:k1:h7 ) is essential for bacterial crossing the blood - brain barrier to 
 cause meningitis .
in contrast , gima 
 is required for the probiotic function of e. 
 coli k24 strain a0 34/86 ( o83:k24:h31 ) , which has been safely and 
 effectively used in czech pediatric clinics since 1967 .
the dual sym - pat 
 properties of microbial determinants were also observed in photorhabdus , which is a genus of gram - negative bacteria 
 mutualistically associated with entomophagous nematodes of the family 
 heterorhabditiae .
a hexa homologous gene from photorhabdus is able to regulate both symbiosis and pathogenesis . 

some microbes exhibit dual behavior as symbionts and pathogens in a manner 
 dependent on the hosts .
sooty mangabey ( sm ) monkeys infected with simian 
 immunodeficiency virus ( siv ) do not develop acquired immunodeficiency syndrome 
 ( aids ) .
in contrast , siv infection of non - natural host monkeys , such as 
 rhesus macaques ( rms ) , causes aids that closely resembles the human disease . 

similarly , polydnaviridae , a family of double - stranded dna viruses , have 
 evolved complex life cycles in which they interact as symbionts with one host 
 and as pathogens 
 with another .
all multicellular organisms , including human and flies , have 
 evolved the conservative innate immune system as a double - edged sword .
it enables 
 the host not only to combat pathogens but also to develop microbial tolerance 
 to cohabit nonpathogenic microbiota by maintaining the homeostatic balance 
 between the host and microorganisms [ 24 , 33 ] .
tlrs play central roles in the 
 activating process of the innate immune system with dual functions .
they have 
 recently been shown to be involved in modulating intestinal homeostasis by 
 recognizing commensal bacteria .
they also sense extracellular pamps by 
 triggering signaling , which results in the activation of proinflammatory ( pi ) pathways 
 .
pi ligands of tlrs may be 
 important for the activation and expansion of natural t regulatory cells 
 ( nattreg ) , which control both deleterious and protective immune responses upon 
 microbial infections .
both innate tlrs and specific t cell receptors ( tcr ) 
 contribute to the dual functions of nattreg .
the full range of the dual 
 ggds in the immune system is unknown so far .
however , it can be expected that 
 the molecular evolution of the dual ggds during the host - microbe coevolution will 
 certainly lead to dynamic changes in the sym - pat   duality .
sym and pat , the fundamental components of microbial infection , 
 can be defined as a function si(x ) 
 or pi(x * ) .
si(x ) and pi(x * ) are continuous functions ranging from 0 to 1 to admit 
 different degrees of sym and pat , respectively ( see figure 4 ) .
si(x ) = 0 and pi(x * ) = 0 indicate that x and  
 x * are perceived to be 
 zero - symbiotic and zero - pathogenic , respectively .
si(x ) = 1 and pi(x * ) = 1 indicate that x and x * are perceived to be completely 
 symbiotic and completely pathogenic , 
 respectively .
if si is close to or equal to 1 , microbial infection is a 
 physiological process .
it is now well accepted that mitochondria were 
 derived from an endosymbiotic relationship with internalized proteobacteria , 
 via a progressive transfer of genetic material .
the symbiotic nitrogen fixation process 
 for converting atmospheric dinitrogen ( n2 ) to ammonia ( nh3 ) 
 is essentially dependent on two partners : the host legume plant and bacteria belonging to 
 the family rhizobiaceae .
if the pi value 
 approaches or reaches the maximum limit , microbial infection is more completely 
 associated with a pathogenic process .
intermediate values of si(x ) and pi(x * ) 
 indicate that x and x * are 
 perceived to be partially symbiotic and partially pathogenic , respectively .
microbial 
 infections induced by conditional pathogens represent a competitive relationship ( see ii or iii in figure 4 ) . 

for example , polydnaviruses have 
 evolved complex life cycles in which they are able to adapt to a mutualistic 
 partnership with one host and become pathogens with another .
the outcome of a game is not 
 only determined by one individual 's choices , but also depends on the strategies 
 used by all the others .
the dynamic sym - pat duality influenced by both microbes 
 and their hosts is the key factor that determines the outcome of a game 
 associated with microbial infection .
one of the most fundamental issues in game 
 theoretical solution concepts is that strategies used by individual players are 
 based on the differences in payoff perceived by them .
fps constitute shared expectations 
 that coordinate the activities of diverse players collectively or independently 
 seeking their goals . by harmonizing anticipated behaviors or responses 
 despite the presence of imperfect information , individuals are able to 
 coordinate their activities towards their ends . in 1960 , schelling classified 
 games into three major categories : pure cooperative game on one side , pure 
 conflict games on the other , and combinations of partial cooperation / partial 
 conflict games in between .
the pure cooperative 
 game models are used for dissecting np - ns interaction problems .
the payoff 
 matrix for a pure np - ns problem would resemble something like that in figure 5(a ) . 

in contrast , the pure up - us interaction , a situation of pure antagonism , is 
 characterized by completely opposing interests , where the pathogenesis of 
 microbial infection is the most predominant event .
the payoff matrix for the 
 pure up - us game would look something like that in figure 5(b ) .
the state of 
 microbial infection has conventionally been characterized as lying on the 
 extreme conflict end .
this depiction comes from the manichaean view of the microbe - human host 
 relationship .
this situation 
 is depicted in figure 5(b ) as a two - player game . in the pure conflict game ,
the relationships 
 between the microbes and their hosts end up in a  war of all against all  in 
 which the payoffs of the outcomes add to zero ( zero - sum ) .
the three microbial 
 community principle and the dynamic sym - pat duality concept would help establish a holistic view of microbial infections .
the 
 cp - cs interaction is a situation where cooperation and conflict coexist . as 
 illustrated in figure 5(c ) , the payoffs for the cp - cs games would lie midway 
 between the pure cooperative and pure conflict games .
the cp - cs problems are 
 microbial dilemmas , in which there is a mixture of mutual dependence and 
 conflict of partnerships and competition . the underlying idea arises naturally 
 from the well - known games for the social dilemmas and the prisoner 's dilemma 
 ( pd ) , in which each player chooses between a cooperating and a defecting 
 strategy . as shown in figure 5(c ) , each player receives a higher 
 playoff by defecting than by cooperating , no matter what the other player 
 chooses .
the cp - cs interactions can coevolve toward two different directions , 
 increasing ( more cooperation ) or decreasing ( more antagonism ) the sp ( see figure 2 ) .
in this paper , focal point 
 theory - based game models are proposed for analysis of the dynamic sym - pat duality 
 in microbial infections .
dspd is the most fundamental problem in infectomics , 
 which is the integration of omics and mathematical / computational approaches . 

there are three types of infectomic approaches that can be used for the control 
 of microbial infections : ecological infectomics , immunoinfectomics , and 
 chemoinfectomics .
developing novel immunological intervention strategies 
 for the prevention and treatment of microbial infections using infectomic 
 signatures and immunomic approaches falls within the field of immunoinfectomics . 

chemoinfectomics represents 
 the most powerful approach to the development of a new generation of drugs for 
 antimicrobial chemotherapy . as microbial 
 infection
is an ecological and evolutionary paradigm which is associated with 
 coevolution between hosts and microbes ( such as human host and microorganisms , 
 phages , and bacteria ) in dynamic ecosystems , two ecological infectomics - based 
 spc approaches ( increasing and decreasing sp ) can be used for rational control 
 of infectious diseases .
the focus 
 in sp increasing approaches is how to transform situations of potential 
 conflict ( pathogenesis ) into cooperation ( symbiosis ) by dissecting the dynamic 
 duality relationships between sym and pat in microbial infections and 
 developing symbiotic agents ( symbiotics ) that favor a healthy symbiosis . 

symbiotics are defined as products that are beneficial to symbiotic ecology of the 
 superorganisms consisting of microbes and their human hosts .
these include 
 microbial ( e.g. , probiotic bacteria ) and nonmicrobial agents ( e.g. , prebiotics ) 

. the introduction 
 of beneficial symbiotics with higher sp in our body should be a very attractive 
 rationale for modulating the microbiota , improving the symbiotic homeostasis of 
 the superorganism , and providing a microbial stimulus to the host immune system 
 against pathogens .
the use of probiotics has been suggested as a promising 
 approach for combating infectious diseases , and delivering drugs and vaccines . 

decreasing sp is another rational strategy for control of microbial 
 infections . as phages , which specifically kill bacteria ,
play an 
 important role in the ecology , evolution , and virulence of a number of 
 pathogens , there is a rational use of phages for treatment and prevention of 
 bacterial infections .
the use of phages to treat bacterial infections has a 
 long history dating back to mid 1910 's .
due to the availability of 
 effective broad - spectrum antibiotics in the early 1940 's , phage therapy was 
 discarded in western medicine at that time .
the rising crisis of antibiotic 
 resistance has recently increased great interest in phages and their use as 
 natural antimicrobial agents to fight microbial infections . compared with 
 commonly used antibiotics ,
recent studies have shown that coinfection with gb virus c ( gbv - c ) is 
 associated with a decreased mortality in hiv - infected patients .
therefore , 
 reducing sp between microbial agents ( such as phages and gbv - c ) and 
 targeted 
 pathogens is another excellent ecological approach for the development of novel 
 antimicrobial agents .
in contrast to the ecological 
 infectomics - based spc approaches that focus on the symbiotic relationships 
 ( such as np - ns and cp - cs interactions ) between the hosts and microbial 
 communities , immunoinfectomics- and chemoinfectomics - based spt approaches 
 emphasize the use of antagonistic relationships ( such as up - us interactions ) 
 between the hosts and microorganisms .
it is important to point out that the spt 
 approaches are intrinsically different from the conventional pathogen - targeting 
 antimicrobial agents , which kill both pathogens and nonpathogens .
the 
 availability of the genomic information from both microbes and their hosts has 
 resulted in exciting new progress in the field of immunoinfectomics .
nanobody 
 ( the smallest fragment of naturally occurring single - domain antibody)-based 
 technologies and immune epitope mapping have emerged as the very powerful tools 
 for the discovery and development of novel antimicrobial agents .
recently , 
 a nanobody - conjugated human trypanolytic factor has been successfully used for 
 an experimental therapy of african trypanosomiasis .
concurrent advances in 
 both high - throughput chemistry and infectomics have given rise to the field of 
 chemoinfectomics for elucidating and validating drug targets , and generating 
 novel therapeutics .
chemoinfectomics refer to the use of small synthetic 
 molecules that are highly specific for defined infectomic targets , for 
 biological function analysis and to discover new drug leads .
the progress 
 towards understanding the dynamic sym - pat duality in microbial infections using 
 focal point theory - based game models will greatly facilitate the use of 
 ecological infectomics , immunoinfectomics , and chemoinfectomics for the 
 rational control of infectious diseases .
 extending along the dynamic continuum from conflict to cooperation , microbial infections always involve symbiosis ( sym ) and pathogenesis ( pat ) . 
 there exists a dynamic sym - pat duality ( dspd ) in microbial infection that is the most fundamental problem in infectomics . 
 dspd is encoded by the genomes of both the microbes and their hosts . 
 three focal point ( fp ) theory - based game models ( pure cooperative , dilemma , and pure conflict ) are proposed for resolving those problems . 
 our health is associated with the dynamic interactions of three microbial communities ( nonpathogenic microbiota ( np ) ( cooperation ) , conditional pathogens ( cp ) ( dilemma ) , and unconditional pathogens ( up ) ( conflict ) ) with the hosts at different health statuses . 
 sym and pat can be quantitated by measuring symbiotic index ( si ) , which is quantitative fitness for the symbiotic partnership , and pathogenic index ( pi ) , which is quantitative damage to the symbiotic partnership , respectively . 
 symbiotic point ( sp ) , which bears analogy to fp , is a function of si and pi . 
 sp - converting and specific pathogen - targeting strategies can be used for the rational control of microbial infections . 
1. INTRODUCTION
2. DEFINITIONS AND METHODS
3. RESULTS
4. DISCUSSION